CN105481862B - The new inhibitor and application thereof of FLT3 kinases - Google Patents

The new inhibitor and application thereof of FLT3 kinases Download PDF

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Publication number
CN105481862B
CN105481862B CN201510547224.9A CN201510547224A CN105481862B CN 105481862 B CN105481862 B CN 105481862B CN 201510547224 A CN201510547224 A CN 201510547224A CN 105481862 B CN105481862 B CN 105481862B
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amino
bases
pyrimidine
pyrazolos
phenoxyphenyls
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CN105481862A (en
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刘静
刘青松
李希祥
王傲莉
吴宏
陈程
王文超
胡晨
赵铮
吴佳昕
刘娟
余凯琳
王伟
王黎
王蓓蕾
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Hefei Youyuan Pharmaceutical Co.,Ltd.
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Hefei Institutes of Physical Science of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides a kind of Azaindole kinase inhibitors comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, metabolin or prodrug.The present invention also provides including formula (I) compound pharmaceutical composition and it is used to prevent or treat cell proliferative disorders and/or the purposes and method of FLT3 associated diseases, the illness especially inhibited in response to FLT3 kinases (especially FLT3/ITD be mutated type kinase).

Description

The new inhibitor and application thereof of FLT3 kinases
Technical field
The present invention relates to the pharmaceutical composition of a kind of novel FLT3 kinase inhibitor compounds including the compound and The FLT3 kinases and/or saltant type FLT3 kinases that cell or subject are reduced or inhibited using these compounds and composition are lived Property and prevent or treat the purposes and method of cell proliferative disorders and/or FLT3 associated diseases in subject.
Background technology
Protein kinase is the enzyme component of signal transduction pathway, is catalyzed the terminal phosphate transesterify of ATP to the junket of protein The hydroxyl of propylhomoserin, serine and/or threonine residues.The overexpression of normal in mammals or mutation protein kinase or Improper expression has become the theme studied extensively, and it is verified play an important role in the development of many diseases, institute It includes diabetes, angiogenesis, psoriasis, restenosis, eye disease, schizophrenia, rheumatoid arthritis, artery congee to state disease Sample hardening, angiocardiopathy and cancer.In short, the inhibitor of protein kinase has special answer in treating human and animal's disease With.
FLT3 (Fms-like tyrosine kinase 3) i.e. FMS samples tyrosine kinase 3, with c-Kit, c-FMS and PDGFR belongs to type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member, The extracellular region that its protein structure is formed including 5 immunoglobulin (Ig) spline structure domains, 1 transmembrane region, 1 membrane-proximal region (JM), And 2 tyrosine kinase (TK) areas that intracellular is separated by kinase insert (S.D.Lyman etc., Oncogene, 1993, 8,815-822).It is found that within 1996 that FLT3 is mutated in AML cells first, mutation type is that internal series-connection repeats (FLT3/ ITD).In recent years, it is very heavy to have confirmed that the activated mutant of FLT3 plays in the generation of AML and the progress of disease for many researchs The pathological effect wanted.AML patient with FLT3/ITD activated mutants is usually with leukocyte counts height, clinical prognosis It is poor, the unique Clinical symptoms such as easy recurrence, and since the detection method of FLT3 activated mutants is simple and practicable, therefore it is more and more Researcher be dedicated to by FLT3 develop into AML conventional detection means be used for instruct the treatment of AML patient and sentencing for prognosis Detection means disconnected and as parvovirus B19, and as the another new target of leukaemic's chemotherapeutics Point.
Haematological malignancies are that the blood of body is formed and immune system, the cancer of marrow and lymphoid tissue.Although In normal marrow, FLT3 expression is only limited to early progenitor cell, but in haematological malignancies, FLT3 be expressed at high levels or Person's FLT3 mutation cause uncontrolled FLT3 receptors and the induction of downstream molecules channel, possible RAS activation.Hematological malignancy is swollen Tumor includes leukaemia, lymthoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Hodgkin lymphoma) and myeloma --- For example, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia or acute myeloid leukaemia (AML), acute early young grain Chronic myeloid leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), chronic neutrophilic cell Leukaemia (CNL), acute undifferentiated cell leukemia (AUL), anaplastic macrocytic lymthoma (ALCL), adult T are thin Born of the same parents ALL, the AML (AML/TMDS) with three pedigrees (trilineage) myelodysplasia, mixed type pedigree leukaemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), Huppert's disease (MM) and spinal cord sarcoma (Kottaridis, P.D., R.E.Gale et al., FLT3 mutations and leukaemia, British Journal of Haematology,2003,122(4):523-38；Ansari-Lari, Ali et al., FLT3mutations in myeloid sarcoma,British Journal of Haematology,2004,126(6):785-91.)。
There are mainly two types of the activated mutants for having confirmed FLT3：Internal series-connection repeats (internal tandem Duplication, ITD) and activation ring in point mutation (point mutation in the activation loop, TKD Point mutation).Both activated mutants of FLT3 are responsible for FLT3 and autophosphorylation occur and then causes FLT3 generation ligands non- The constitutively activated of dependence further activates signal transduction abnormal downstream, promotes to be proliferated and inhibit apoptosis to play Effect so that with this mutant phenotype leukaemic's clinical prognosis it is poor.
Research hotspot is become to the targeted inhibition of FLT3 and saltant type FLT3 at present, small molecule tyrosine is predominantly developed and swashs Enzyme inhibitor inhibits its activity by competing ATP-binding site with FLT3 tyrosine kinase.Clinical suppression is come at present The kinase inhibitor of FLT3 processed has AC220 etc..
Invention content
The present invention provides a kind of novel FLT3 kinase inhibitors comprising the compound of formula (I) or its is pharmaceutically acceptable Salt, solvate, isomers, ester, acid, metabolin or prodrug：
Wherein：
M is selected from an integer of 1 or 2；
N is the integer selected from 0-4；
X is N or CH, and when X is N, Y is chemical bond, when X is CH, Y NH；
Z is selected from CH2、
R is selected from the C1-C8 alkyl that amino, unsubstituted or carbon atom optionally replace by 1 to 3 independent R1, unsubstituted Or C3-C8 naphthenic base that carbon atom is optionally replaced by 1 to 3 independent R1, unsubstituted or carbon atom optionally by 1 to 3 The C1-C8 halogenated alkyls of independent R1 substitution, unsubstituted or carbon atom are optionally replaced or hetero atom by 1 to 3 independent R1 The C1-C8 cyanogen optionally optionally replaced by 1 to 3 independent R1 by C1-C8 aminoalkyls that R2 replaces, unsubstituted or carbon atom C1-C8 hydroxy alkyls that base alkyl, unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1, unsubstituted or carbon are former The sub C1-C8 alkoxyl optionally replaced by 1 to 3 independent R1, unsubstituted or carbon atom are optionally by 1 to 3 independent R1 C3-C8 Heterocyclylalkyls that substitution or hetero atom are optionally replaced by R2, unsubstituted or carbon atom is optionally by 1 to 3 independent R1 Substituted aryl, unsubstituted or carbon atom are optionally by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 heteroaryl Base, carbamoyl, unsubstituted or carbon atom be not optionally by C1-C8 alkyl formyl radicals that 1 to 3 independent R1 replaces, take C3-C8 naphthenic base formoxyl, unsubstituted or carbon atom generation or that carbon atom is optionally replaced by 1 to 3 independent R1 are optional It is former by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 C3-C8 Heterocyclylalkyls formoxyl, unsubstituted or carbon Son is optionally optionally taken by 1 to 3 independent R1 by aryl formoxyl that 1 to 3 independent R1 replaces, unsubstituted or carbon atom The C1-C8 that C1-C8 alkyl aminos (C1-C8) alkyl, the unsubstituted or carbon atom in generation are optionally replaced by 1 to 3 independent R1 C3-C6 naphthenic base (the C1-C8 that alkyl (C3-C6 naphthenic base), unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1 Alkyl), unsubstituted or carbon atom is optionally by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 C1-C8 alkyl (C3-C6 Heterocyclylalkyls), unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1 or hetero atom is optionally replaced by R2 C3-C6 Heterocyclylalkyls (C1-C8 alkyl), the C1-C8 alkane that is optionally replaced by 1 to 3 independent R1 of unsubstituted or carbon atom Base (aryl), unsubstituted or carbon atom are optionally by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 C1-C8 C1-C8 aminoalkyl (the amino that alkyl (heteroaryl) and unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1 Formoxyl)；
R1 is selected from halogen, amino, nitro, cyano, hydroxyl, C1-C8 alkyl, C3-C8 naphthenic base, C1-C8 alkoxyl, virtue The C1-C8 alkyl that base, hetero atom are optionally optionally replaced by R2 by heteroaryl, C1-C8 alkoxyl carbonyl, hetero atom that R2 replaces The C1-C8 alkyl (C3-C6 Heterocyclylalkyls) that (heteroaryl) and hetero atom are optionally replaced by R2；
R2 is selected from amino protecting group, C1-C8 alkyl and C1-C8 alkoxyl carbonyl.Amino protecting group is independently selected from tertiary fourth Oxygen carbonyl (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl (FMOC), benzyl (Bn) and p-methoxyphenyl (PMP).
In some embodiments, n is preferably 1 or 2.
In some embodiments, Z is preferably
In some embodiments, R be preferably selected from substituted or unsubstituted C1-C6 alkyl (such as methyl, ethyl, n-propyl, Isopropyl, normal-butyl, isobutyl group, tertiary butyl, n-pentyl, isopentyl and neopentyl etc.), C1-C4 halogenated alkyls (such as chloro first Base, trifluoromethyl, trichloromethyl, Chloroethyl, bromoethyl, trifluoroethyl, trifluoroethyl, chloro propyl, Bromopropyl, chlorine For butyl and bromobutyl etc.), C3-C6 naphthenic base (such as cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl), amino, amino Formoxyl, C1-C6 aminoalkyls (methyl, ethyl, propyl, butyl and the amyl that such as any carbon atom is replaced by amino, and N Optionally replaced by R2 such as C1-4 alkyl and amino protecting group), heteroaryl (such as pyridyl group, pyrimidine radicals, isoxazolyls and benzo Er Evil cyclopentadienyls etc., and carbon atom is optionally replaced by amino), C3-C6 Heterocyclylalkyls (such as piperazinyl and piperidyl and N atoms Optionally replaced by C1-C4 alkyl and C1-C4 alkoxy carbonyls), aryl (such as phenyl, and carbon atom is optionally by C1-C4 alkoxy carbonyls Base replaces methyl (piperazinyl) methyl), C1-C4 cyanoalkyls (such as cyano methyl, cyano ethyl, cyanopropyl and cyanogen Base butyl etc.), two (C1-C4 alkyl)-N- (C1-C4) alkyl (such as dimethylamino methyl, Diethylaminomethyl, dimethylamino second Base, diethyllaminoethyl, dimethylamino-propyl and dimethylaminobutyl etc.), (such as any carbon atom is by hydroxyl for C1-C6 hydroxy alkyls Methyl, ethyl, propyl, butyl and the amyl etc. of base substitution, and carbon atom is optionally replaced by amino), C1-C4 alkyl (C3-C6 Heterocyclylalkyl) (such as morpholinyl methyl, piperizinylmethyl and piperazinyl, and N atoms are optionally replaced by C1-C4 alkyl), C1-C4 alkyl (C3-C6 naphthenic base) (such as Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclopropylethyl, cyclobutyl second Base, cyclopentyl ethyl, Cyclopropylpropyl and cyclopropyl butyl etc.), (such as either carbon is former for C1-C4 aminoalkyls (carbamoyl) Ethyl (carbamoyl) and propyl (carbamoyl) that son is replaced by amino etc.), (such as carbon is former for C1-C4 alkyl (heteroaryl) Imidazole ethyl, indolylethyl, imidazopropionyl and the indoles propyl etc. that son is optionally replaced by amino) and C1-C4 alkyl (aryl) (benzyl, phenethyl and phenylpropyl that such as carbon atom is optionally replaced by amino, hydroxyl).
In some embodiments, 1 m, and X is N, Y is chemical bond, and the compound of the present invention is indicated by formula (II)：
Wherein, n, Z and R are as hereinbefore defined.
In yet another embodiment, 2 m, and X is N, Y is chemical bond, and the compound of the present invention is indicated by formula (III)：
Wherein, n, Z and R are as hereinbefore defined.In this embodiment, n is preferably 1.
In another embodiment, 2 m, and X is CH, Y NH, the compound of the present invention is by formula (IV) expression：
Wherein, n, Z and R are as hereinbefore defined.In this embodiment, n is preferably 1.
On the other hand, the present invention provides a kind of pharmaceutical composition comprising at least one of therapeutically effective amount carries herein The compound of confession or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, metabolin or prodrug and pharmacy can connect The carrier or excipient received, and optional other therapeutic agents.
It yet still another aspect, the present invention provides a kind of formula (I) of the present invention, (II), (III) or (IV) compound or its pharmacy The preparation method of acceptable salt, solvate, isomers, ester, acid, metabolin or prodrug.
It yet still another aspect, the present invention relates to formula (I), (II), (III) or (IV) compound or its pharmaceutically acceptable salt, Solvate, isomers, ester, acid, metabolin or prodrug reduce or inhibit FLT3 kinases and/or saltant type in vivo or in vitro The purposes of FLT3 kinase activities.
It yet still another aspect, the present invention relates to formula (I), (II), (III) or (IV) compound or its pharmaceutically acceptable salt, Solvate, isomers, ester, acid, metabolin or prodrug or the medicine group for including formula (I), (II), (III) or (IV) compound Close purposes of the object in preparing the drug for treating cell proliferative disorders and/or FLT3 associated diseases.
Particularly, the sick illness of institute is in response to FLT3 or saltant type FLT3 kinase inhibitions.FLT3 mutation include ITD mutation with TKD point mutation, especially FLT3/ITD are mutated.
Description of the drawings
It is right in MV 4-11 and MOLM-14 cells that compound 22, compound 77 and compound 84 is shown respectively in Fig. 1 a to 1f The influence of albumen and associated signal paths relatively closely related FLT3.
External inhibition of the compound of the present invention to FLT3, FLT3/ITD and BTK protein kinase is shown respectively in Fig. 2 a to 2c Active (enzyme activity) testing result.
Fig. 3 a to 3b show compound 22 and compound 84 respectively to the Apoptosis of MV4-11, MOLM-13 cell strain It influences.
Fig. 4 a to 4b show the influence of compound 22 and compound 84 to the cell cycle distribution of MV4-11 cell strains.
Fig. 5 a to 5b show the tumour suppression of compound 22 and compound 77 in MOLM-14 cell tumours transplant mouse model Effect processed.
Specific implementation mode
Term
Unless otherwise defined, all scientific and technical terminologies used herein all have the skill with claimed theme fields Art personnel are commonly understood by identical meaning.
Unless otherwise indicated, the present invention is using the mass spectrum within the scope of art technology, NMR, HPLC, protein chemistry, life The conventional methods such as object chemistry, recombinant DNA technology and pharmacology.Unless provide specific definition, otherwise with analysis described herein The chemically relevant name of chemistry, synthetic organic chemistry and medicine and pharmaceutical chemistry etc. and laboratory operation and technology, are these Known to field technology personnel.In general, aforementioned techniques and step can be by well-known in the art and various one As conventional method described in document and more specific document implement, these documents are cited and discuss in the present specification.
" alkyl " refers to aliphatic hydrocarbon groups, can be the alkyl of branch or straight chain.According to structure, alkyl can be unit price Group or bivalent radical (i.e. alkylidene).In the present invention, alkyl is preferably " low alkyl group " with 1-6 carbon atom.Allusion quotation The alkyl of type includes but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, hexyl etc..
" alkoxy " refers to-O- alkyl, and wherein alkyl is as defined herein.Typical alkoxy includes but not limited to methoxy Base, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy etc..
" alkoxyalkyl " refers to that alkyl defined herein is replaced by alkoxy defined herein.
Terms used herein " cyano " refer to formula-CN groups.
Term " amino " refers to group-NH2。
Term " alkyl amino " refers to further by one or two alkyl-substituted amino-substituent, in particular to base Group-NRR ', wherein R and R ' are each independently selected from hydrogen or low alkyl group, and condition is that-NRR ' is not -NH2.Term " the virtue of this paper Alkyl amino " refer to wherein R be loweraralkyl and R ' be hydrogen, low alkyl group, aryl or loweraralkyl group-NRR '. Term " aminoalkyl " refers to the alkyl substituent further replaced by one or more amino.Term " hydroxyalkyl " or " hydroxyl Alkyl " refers to the alkyl substituent further replaced by one or more hydroxyls.Term " cyanoalkyl " refers to further by one The alkyl substituent of a or multiple cyano substitutions.Term " alkyl-carbonyl " refers to further by an alkyl-substituted carbonyl.Art Language " Alkylcarbonylalkyl " refers to the alkyl further replaced by an alkyl-carbonyl.Term " alkoxy carbonyl " refers to further The carbonyl replaced by an alkoxy.Alkyl amino, aminoalkyl, hydroxy alkyl, cyanoalkyl, alkyl-carbonyl, alkyl-carbonyl Alkyl or aryl part in alkyl and alkoxy carbonyl can be optionally substituted by one or more substituents.
" alkylaminoalkyl group " refers to that alkyl defined herein is replaced by alkyl amino defined herein.
Term " aromatic radical ", which refers to planar rings, to be had the pi-electron system of delocalization and contains 4n+2 pi-electron, and wherein n is Integer.Fragrant basic ring can be by five, six, seven, eight, nine or more than nine atomic buildings.Aromatic radical can optionally replace.Art Language " aromatic radical " includes isocyclic aryl (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaryl perfume base ") group (such as pyrrole Pyridine).The term includes monocycle or polycyclic (ring for the sharing adjacent carbon atom pair) group of condensed ring.
Terms used herein " aryl " refer to that the atom that each in fragrant basic ring constitutes ring is carbon atom.Aryl rings By five, six, seven, eight, nine or nine atomic buildings can be more than.Aryl can optionally replace.The example of aryl include but It is not limited to phenyl, naphthalene, phenanthryl, anthryl, fluorenyl and indenyl.According to structure, aryl can be monoradical or bivalent radical (i.e. Arlydene).
" alkyl (aryl) " or " aralkyl " refer to that alkyl defined herein is replaced by aryl defined herein.It is non-limiting Alkyl (aryl) include benzyl, phenethyl etc..
Term " naphthenic base " refers to monocycle or polycyclic group, only contains carbon and hydrogen.Naphthenic base includes having 3-8 annular atom Group.According to structure, naphthenic base can be monoradical or bivalent radical (such as cycloalkylidene).In the present invention, cycloalkanes Base is preferably the naphthenic base with 3-8 carbon atom, more preferably " low-grade cycloalkyl " with 3-6 carbon atom.
" alkyl (naphthenic base) " or " cycloalkyl-alkyl " refer to that alkyl defined herein is replaced by naphthenic base defined herein. Unrestricted alkyl (naphthenic base) includes Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl etc..
Terms used herein " miscellaneous alkyl " refer to that one or more of alkyl defined herein skeletal chain atoms are miscellaneous Atom, such as oxygen, nitrogen, sulphur, silicon, phosphorus or combination thereof.The hetero atom (one or more) can be located inside miscellaneous alkyl Any position or in the position that miscellaneous alkyl is connected with the rest part of molecule.
Term " heteroaryl " refers to that aryl includes one or more ring hetero atoms selected from nitrogen, oxygen and sulphur.Containing N " heteroaryls Base " refers to partly that at least one skeletal atom is nitrogen-atoms in aromatic radical middle ring.According to structure, heteroaryl can be monovalent radical Group or bivalent radical (i.e. inferior heteroaryl).The example of heteroaryl include but not limited to pyridyl group, imidazole radicals, pyrimidine radicals, pyrazolyl, Triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyls, thiazolyl, oxazolyls, isothiazolyl, pyrrole radicals, quinoline Quinoline base, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, iso-indoles Base, pteridyl, purine radicals, oxadiazolyls, thiadiazolyl group, furyl, benzofuranyl, benzothienyl, benzothiazolyl, benzene Bing oxazolyls, quinazolyl, naphthyridines base and furopyridyl etc..
Terms used herein " Heterocyclylalkyl " refer to that one or more atoms for constituting ring are to be selected from non-aromatic basic ring The hetero atom of nitrogen, oxygen and sulphur.Heterocycloalkyl ring can be by three, four, five, six, seven, eight, nine or more than nine atomic buildings.Heterocycle Alkyl ring can optionally replace.The example of Heterocyclylalkyl includes but not limited to lactams, lactone, ring Asia glue, epithio generation Asia Amine, cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, oxinane, piperidines, 1,3- bioxin, 1,3- dioxanes, 1,4- bis- Evil English, 1,4- dioxanes, piperazine, 1,3- thioxane, 1,4- oxathiins, 1,4- thioxane, tetrahydrochysene- 1,4- thiazines, 2H-1,2- oxazines, maleimide, succinimide, barbiturates, thiobarbituricacidα-, dioxopiperazine, Hydantoins, dihydrouracil, morpholine, trioxanes, hexahydro -1,3,5- triazines, thiophane, tetrahydrofuran, pyrrolin, pyrroles Alkane, imidazolidine, pyrrolidones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxole, 1,3- dioxanes Pentane, 1,3- dithioles, 1,3- dithiolane, isoxazoline, isoxazole alkyl, oxazoline, oxazolidine, oxazolidines Ketone, thiazoline, thiazolidine and 1,3- oxathiolanes.According to structure, Heterocyclylalkyl can be monoradical or bivalent radical (i.e. sub- Heterocyclylalkyl).
Term " alkyl (heteroaryl) " or " heteroaryl alkyl " refer to alkyl defined herein by heteroaryl defined herein Substitution.
Term " alkyl (Heterocyclylalkyl) " or " hetercycloalkylalkyl " refer to alkyl defined herein by defined herein miscellaneous Naphthenic base replaces.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " halogenated alkyl ", " alkoxy of halogen substitution " and " miscellaneous alkyl of halogen substitution " include alkyl, alkoxy or miscellaneous The structure of alkyl, wherein at least one hydrogen are replaced by halogen atom.In some embodiments, if two or more hydrogen atom quilts Halogen atom is replaced, and the halogen atom is same or different to each other.
Term " acyl group " refers to that organic or inorganic oxyacid removes remaining monovalent radical after hydroxyl, general formula R-M (O)-, wherein M is usually C.
Term " carbonyl " is the organo-functional group (C=O) being formed by connecting by double bond by two kinds of atoms of carbon and oxygen.
Term " substituted " refers to mentioned group replace by one or more additional groups, it is described additionally Group is respectively and independently selected from alkyl, naphthenic base, aryl, heteroaryl, hydroxyl, alkoxy, cyano, halogen, amide groups, nitre Base, halogenated alkyl, amino, alkoxy carbonyl, alkyl (heteroaryl), alkyl (Heterocyclylalkyl) etc..
" inhibition ", " inhibition " or " inhibitor " of terms used herein kinases refers to that phosphate transferase activity is pressed down System.
" metabolin " of compound disclosed herein is the derivative of the compound formed when the compound is metabolized.Art Language " active metabolite " refers to the biologically active derivatives of the compound formed when the compound is metabolized.Art used herein Language " is metabolized ", refer to the process of predetermined substance by organism transform summation (includes but not limited to hydrolysis and by enzymatic Reaction, such as oxidation reaction).Therefore, enzyme can generate specific structure and be changed into compound.For example, Cytochrome P450 It is catalyzed various oxidations and reduction reaction, while the glucuronic acid molecule of diphosphate glucose sweet acid based transferase catalytic activation is extremely The conversion of aromatic alcohol, aliphatic alcohol, carboxylic acid, amine and free sulfydryl.The further information of metabolism can be from《The Pharmacological Basis of Therapeutics》, the 9th edition, McGraw-Hill (1996) is obtained.It is disclosed herein The metabolin of compound can be by giving compound to host and analyzing tissue sample from the host or by that will change Object is closed to be incubated in vitro with liver cell and analyze gained compound to differentiate.Both methods is all known in the art. In some embodiments, the metabolin of compound is to be formed by oxidation process and corresponding with corresponding hydroxy-containing compounds. In some embodiments, compound is metabolized as pharmaceutical active metabolite.Terms used herein " adjusting ", refer to directly or It connects and interacts with target, to change the activity of target, for example only, including intensifier target target activity, suppression target Activity, limit target target activity or the activity for extending target.
Term " prodrug " includes the compound with the part that can be metabolized in vivo.In general, prodrug is by esterase or leads to It crosses other mechanism and is metabolized active drugs in vivo.The example of prodrug and application thereof is known (see, for example, Berge in the art Et al. (1977) " Pharmaceutical Salts ", J.Pharm.Sci.66:1-19).Can compound be finally recovered and Prodrug is prepared in situ during purifying, or by individually making the compound of purifying with its free acid form or hydroxyl and suitably Esterifying agent reacts to prepare.Hydroxyl can handle through carboxylic acid and be converted into ester.The example of prodrug moiety includes substitution and is not taken Generation, branch or unbranched lower alkyl ester moieties (such as propionic ester), low-grade alkenyl ester, two-lower alkyl-amino lowers Arrcostab (such as dimethyl aminoethyl ester), acyl amino lower alkyl esters (such as acetoxy-methyl ester), acyloxy are low Grade Arrcostab (such as oxy acid methyl neopentyl ester), aryl ester (phenylester), aromatic yl elementary alkyl ester (such as benzyl ester), substitution (such as being replaced by methyl, halogen or methoxy substitution base) aryl and aromatic yl elementary alkyl ester, amide, low alkyl group acyl Amine, two lower alkyls and hydroxy amide.Preferred prodrug moiety is propionic ester and acyl ester.It is also included within and passes through it in vivo Its mechanism is converted to the prodrug of active form.In some respects, the compound of the present invention is the prodrug of arbitrary this paper general formulas.
Term " isomers " refers to that chemical composition is identical but compound that atom or group are different on space arrangement, meaning Including diastereoisomer, enantiomter, region isomer (regioisomers), constitutional isomer, rotational isomer, Tautomer etc..For containing the compound of one or more Stereocenters (stereogenic center), such as chirality Compound can implement the present invention's using enantiomeric enrichment compound, racemic modification or non-enantiomer mixture Method.
Terms used herein " target protein " refer to the protein molecule that can be combined by selective binding compounds or portion Divide protein.In some embodiments, target protein is FLT3.
IC used herein50The 50% of ceiling effect is obtained in the analysis for referring to the effect as measurement inhibits specific Test amount, concentration or the dosage of compound.
EC used herein50Refer to dosage, concentration or the amount for measuring compound, particular assay compound is caused to induce, The dose-dependant reaction of 50% maximum expression of stimulation or the specific reaction reinforced.
The novel kinase inhibitor of the present invention
The present invention provides a kind of novel FLT3 kinase inhibitors comprising the compound of formula (I) or its is pharmaceutically acceptable Salt, solvate, isomers, ester, acid, metabolin or prodrug：
Wherein：
M is selected from an integer of 1 or 2；
N is the integer selected from 0-4；
X is N or CH, and when X is N, Y is chemical bond, when X is CH, Y NH；
Z is selected from CH2、
R is selected from the C1-C8 alkyl that amino, unsubstituted or carbon atom optionally replace by 1 to 3 independent R1, unsubstituted Or C3-C8 naphthenic base that carbon atom is optionally replaced by 1 to 3 independent R1, unsubstituted or carbon atom optionally by 1 to 3 The C1-C8 halogenated alkyls of independent R1 substitution, unsubstituted or carbon atom are optionally replaced or hetero atom by 1 to 3 independent R1 The C1-C8 cyanogen optionally optionally replaced by 1 to 3 independent R1 by C1-C8 aminoalkyls that R2 replaces, unsubstituted or carbon atom C1-C8 hydroxy alkyls that base alkyl, unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1, unsubstituted or carbon are former The sub C1-C8 alkoxyl optionally replaced by 1 to 3 independent R1, unsubstituted or carbon atom are optionally by 1 to 3 independent R1 C3-C8 Heterocyclylalkyls that substitution or hetero atom are optionally replaced by R2, unsubstituted or carbon atom is optionally by 1 to 3 independent R1 Substituted aryl, unsubstituted or carbon atom are optionally by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 heteroaryl Base, carbamoyl, unsubstituted or carbon atom be not optionally by C1-C8 alkyl formyl radicals that 1 to 3 independent R1 replaces, take C3-C8 naphthenic base formoxyl, unsubstituted or carbon atom generation or that carbon atom is optionally replaced by 1 to 3 independent R1 are optional It is former by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 C3-C8 Heterocyclylalkyls formoxyl, unsubstituted or carbon Son is optionally optionally taken by 1 to 3 independent R1 by aryl formoxyl that 1 to 3 independent R1 replaces, unsubstituted or carbon atom The C1-C8 that C1-C8 alkyl aminos (C1-C8) alkyl, the unsubstituted or carbon atom in generation are optionally replaced by 1 to 3 independent R1 C3-C6 naphthenic base (the C1-C8 that alkyl (C3-C6 naphthenic base), unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1 Alkyl), unsubstituted or carbon atom is optionally by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 C1-C8 alkyl (C3-C6 Heterocyclylalkyls), unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1 or hetero atom is optionally replaced by R2 C3-C6 Heterocyclylalkyls (C1-C8 alkyl), the C1-C8 alkane that is optionally replaced by 1 to 3 independent R1 of unsubstituted or carbon atom Base (aryl), unsubstituted or carbon atom are optionally by 1 to 3 independent R1 replaces or hetero atom is optionally replaced by R2 C1-C8 C1-C8 aminoalkyl (the amino that alkyl (heteroaryl) and unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1 Formoxyl)；
R1 is selected from halogen, amino, nitro, cyano, hydroxyl, C1-C8 alkyl, C3-C8 naphthenic base, C1-C8 alkoxyl, virtue The C1-C8 alkyl that base, hetero atom are optionally optionally replaced by R2 by heteroaryl, C1-C8 alkoxyl carbonyl, hetero atom that R2 replaces The C1-C8 alkyl (C3-C6 Heterocyclylalkyls) that (heteroaryl) and hetero atom are optionally replaced by R2；
R2 is selected from amino protecting group, C1-C8 alkyl and C1-C8 alkoxyl carbonyl.Amino protecting group is independently selected from tertiary fourth Oxygen carbonyl (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl (FMOC), benzyl (Bn) and p-methoxyphenyl (PMP).
In some embodiments, n is preferably 1 or 2.
In some embodiments, Z is preferably
In some embodiments, R be preferably selected from substituted or unsubstituted C1-C6 alkyl (such as methyl, ethyl, n-propyl, Isopropyl, normal-butyl, isobutyl group, tertiary butyl, n-pentyl, isopentyl and neopentyl etc.), C1-C4 halogenated alkyls (such as chloro first Base, trifluoromethyl, trichloromethyl, Chloroethyl, bromoethyl, trifluoroethyl, trifluoroethyl, chloro propyl, Bromopropyl, chlorine For butyl and bromobutyl etc.), C3-C6 naphthenic base (such as cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl), amino, amino Formoxyl, C1-C6 aminoalkyls (methyl, ethyl, propyl, butyl and the amyl that such as any carbon atom is replaced by amino, and N Optionally replaced by R2 such as C1-4 alkyl and amino protecting group), heteroaryl (such as pyridyl group, pyrimidine radicals, isoxazolyls and benzo Er Evil cyclopentadienyls etc., and carbon atom is optionally replaced by amino), C3-C6 Heterocyclylalkyls (such as piperazinyl and piperidyl and N atoms Optionally replaced by C1-C4 alkyl and C1-C4 alkoxy carbonyls), aryl (such as phenyl, and carbon atom is optionally by C1-C4 alkoxy carbonyls Base replaces methyl (piperazinyl) methyl), C1-C4 cyanoalkyls (such as cyano methyl, cyano ethyl, cyanopropyl and cyanogen Base butyl etc.), two (C1-C4 alkyl)-N- (C1-C4) alkyl (such as dimethylamino methyl, Diethylaminomethyl, dimethylamino second Base, diethyllaminoethyl, dimethylamino-propyl and dimethylaminobutyl etc.), (such as any carbon atom is by hydroxyl for C1-C6 hydroxy alkyls Methyl, ethyl, propyl, butyl and the amyl etc. of base substitution, and carbon atom is optionally replaced by amino), C1-C4 alkyl (C3-C6 Heterocyclylalkyl) (such as morpholinyl methyl, piperizinylmethyl and piperazinyl, and N atoms are optionally replaced by C1-C4 alkyl), C1-C4 alkyl (C3-C6 naphthenic base) (such as Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclopropylethyl, cyclobutyl second Base, cyclopentyl ethyl, Cyclopropylpropyl and cyclopropyl butyl etc.), (such as either carbon is former for C1-C4 aminoalkyls (carbamoyl) Ethyl (carbamoyl) and propyl (carbamoyl) that son is replaced by amino etc.), (such as carbon is former for C1-C4 alkyl (heteroaryl) Imidazole ethyl, indolylethyl, imidazopropionyl and the indoles propyl etc. that son is optionally replaced by amino) and C1-C4 alkyl (aryl) (benzyl, phenethyl and phenylpropyl that such as carbon atom is optionally replaced by amino, hydroxyl).
In some embodiments, 1 m, and X is N, Y is chemical bond, and the compound of the present invention is indicated by formula (II)：
Wherein, n, Z and R are as hereinbefore defined.In this embodiment, n is preferably 1 or 2.
In yet another embodiment, 2 m, and X is N, Y is chemical bond, and the compound of the present invention is indicated by formula (III)：
Wherein, n, Z and R are as hereinbefore defined.In this embodiment, n is preferably 1.
In another embodiment, 2 m, and X is CH, Y NH, the compound of the present invention is by formula (IV) expression：
Wherein, n, Z and R are as hereinbefore defined.In this embodiment, n is preferably 1.
Compound involved in the present invention with chirality, configuration can be arbitrary configuration or mixed racemic modification.
On the one hand, it preferably provides herein and selects following compound, the structure of these preferred compounds is as shown in table 1.
For each variable, the arbitrary of above-mentioned group combines also among considering herein.It can be understood that：It is carried herein Substituent group and substitute mode in the compound of confession can be selected by those skilled in the art, in order to provide chemically stable And compound that techniques known in the art and technology set forth herein can be used to synthesize.
Described herein is novel kinase inhibitor.The pharmaceutically acceptable salt, molten of this compound has been also described herein Agent compound, isomers, ester, acid, pharmaceutical active metabolite and prodrug.
In other or further embodiment, by compound described herein give after organism in need Its metabolism in vivo generates metabolin, and generated metabolin is subsequently used for generating desired effect, including desired therapeutic effect.
Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmaceutically acceptable salt Type includes but not limited to：(1) acid-addition salts, by by the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction It is formed, described inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc.；Or formed with organic acid reaction, it is described Organic acid for example acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, Succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4- hydroxy benzoyls) benzoic acid, Chinese cassia tree Acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acids, 2- ethylenehydrinsulfonic acids, benzene sulfonic acid, toluenesulfonic acid, 4- methyl Bicyclic-[2.2.2] oct-2-ene -1- formic acid, 2- naphthalene sulfonic acids, butylacetic acid, glucoheptonic acid, 4,4' methylene bis-(3- hydroxyls Base -2- alkene -1- formic acid), 3- phenylpropionic acids, trimethylace tonitric, dodecyl sulphate, gluconic acid, glutamic acid, salicylic acid, hydroxyl Naphthoic acid, stearic acid, muconic acid etc.；(2) base addition salts, the shape when acid proton in parent compound is replaced by metal ion At, such as alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion；Or match with organic base Position.Acceptable organic base includes ethanol amine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucose osamines, etc..It can connect The inorganic base received includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
The corresponding ion balance of pharmaceutically acceptable salt can analyze and be identified using various methods, the method includes But be not limited to ion-exchange chromatography, ion chromatography, Capillary Electrophoresis, inductively coupled plasma, atomic absorption spectrum, mass spectrum or Any combination of them.
The salt is recycled using at least one of following technology：Filtering is then filtered, evaporation of the solvent with non-solvent precipitation, Or desivac is used in the case of aqueous solution.
Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can be completed using multiple technologies, described Technology includes but not limited to heat analysis, X-ray diffraction, spectrum, microscopy, elemental analysis.The various spectral techniques used Including but not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).Various microscopies include but not limited to IR Microscopy and Raman (Raman) microscopy.
The medical composition and its use of the present invention
The present invention also relates to pharmaceutical compositions, they include formula (I), (II), (III) or (IV) compound or its pharmacy can Salt, solvate, isomers, ester, acid, metabolin or the prodrug of receiving are as active constituent and pharmaceutically acceptable carrier Or excipient, and optional other therapeutic agents.
Formula (I), (II), (III) or (IV) compound or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, It metabolin or prodrug and is hereinafter also known as " substance of the invention " including its pharmaceutical composition.
The substance of the present invention can be used to treat or prevent cell proliferative disorders and/or FLT3 associated diseases, especially ring It should inhibit in protein tyrosine kinase, the disease of especially FLT3 or saltant type FLT3 kinase inhibitions.FLT3 mutation include ITD mutation With TKD point mutation, especially ITD mutation." treatment " of the present invention can be therapeutic (such as symptomatic treatment) and/or preventative 's.The substance of the present invention can preferably treat or prevent and the relevant illnesss of FLT3, particularly preferably treatment or prevention and saltant type The relevant illnesss of FLT3/ITD.
Specifically, the substance of the present invention can be used to treat or prevent cell proliferative disorders, selected from benign or malignant swollen Tumor, including but not limited to：Presence or development, B cell lymph cancer, sarcoma, lymthoma, the leaching of diffusivity large B cell of entity tumor Bar tumor, follicular lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, the white blood of B cell prolymphocyte Sick, lymphoplasmacytic lymphoma/macroglobulinemia Waldenstron (acroglobulinemia)、 Splenic marginal zone lymthoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymph node marginal zone B are thin Born of the same parents' lymthoma, lymphoma mantle cell (mantle cell lymphoma), mediastinum (thymus gland) large B cell lymphoid tumor, intravascular big B Cell lymphoma, lymphoma primary effusion, Burkitt lymphoma (Burkitt lymphoma), leukaemia, lymthoma sample Granulomatosis, breast ductal cancer, lobular carcinoma, gland cancer, melanoma, B cell proliferative disease, the cancer of the brain, kidney, liver cancer, on kidney Gland cancer, carcinoma of urinary bladder, breast cancer, lymph cancer, gastric cancer, stomach neoplasm, cancer of the esophagus, oophoroma, colorectal cancer, prostate cancer, cancer of pancreas, Lung cancer, carcinoma of vagina, film gland cancer, thyroid cancer, neck cancer, the cancer of CNS, glioblastoma, myeloproliferative disease, spongioblast Tumor, Huppert's disease, human primary gastrointestinal cancers, colorectal cancer, H/N tumors, brain tumor, epidermal hyper-proliferative, psoriasis, prostate increase Raw, tumor formation, tumor formation, lymthoma, breast cancer or the leukaemia of epithelial character or similar disease, or combinations thereof.
The substance of the present invention can also be used to treat or prevent FLT3 associated diseases, especially saltant type FLT3/ITD related diseases Disease, including but not limited to：Haematological malignancies include leukaemia, lymthoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as For Hodgkin lymphoma) and myeloma --- for example, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), chronic neutrophilic chronic myeloid leukemia (CNL), acute undifferentiated cell leukemia (AUL), anaplastic macrocytic Lymthoma (ALCL), human adult T cell ALL, with three pedigrees (trilineage) myelodysplasia AML (AML/TMDS), Mixed type pedigree leukaemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), Huppert's disease (MM) and spinal cord sarcoma, chronic lymphocytic leukemia, diffusivity large B cell lymphoid tumor (DLBCL), follicular lymphoma or slow Property lymphocytic leukemia, lymphoma mantle cell (mantle cell lymphoma), mediastinum (thymus gland) large B cell lymphoid tumor, Intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma (Burkitt lymphoma) or similar Disease, or combinations thereof.
It is preferred that warm-blooded animal, especially mankind's enteral administration such as nose, oral cavity, rectum or composition being especially administered orally and Parenteral administration is for example intravenous, intramuscular or subcutaneous administration composition.The dose-dependant of active constituent is in institute's disease to be treated With kind, its age, weight and individual condition, individual pharmacokinetic data available and administering mode.
Described pharmaceutical composition can optionally be used in combination with known treatment methods, such as the application of hormone or radiation. Other therapeutic agents include, for example, cytostatics, other antiproliferatives.
This kind of antiproliferative includes but not limited to aromatization enzyme inhibitor, antiestrogenic, topoisomerase I inhibitor, opens up Flutter isomerase II inhibitor, microtubule active agent, alkylating agent, inhibitors of histone deacetylase, farnesyl transferase inhibitor, Cox 2 inhibitor, mTOR inhibitors, anti-tumor formative antimetabolite, platinum compounds, reduces protein kinase activity at MMP inhibitor Compound and further anti-angiogenic compounds, GnRF agonist, antiandrogen, Bengamide, bis-phosphonic acids compounds, steroids, anti proliferative antibody, 17- (allyl amido) -17- de-methoxies Ge Erde Mycin (17-AAG) and Temozolomide (TMEMODAL).
Terms used herein " aromatization enzyme inhibitor " is related to inhibiting estrogen production, namely substrates androstenedione and female The compound of diketone conversion.The term includes but not limited to steroids, especially Exemestane and formestane, and is especially non-class Sterol, especially aminoglutethimide, R 83842, Fadrozole, Anastrozole, very especially Letrozole.Exemestane for example can be with Its commercial form is administered, such as trade mark is AROMASINTM.Formestane can be for example administered with its commercial form, such as trade mark is LENTARONTM.Fadrozole can be for example administered with its commercial form, such as trade mark is AFEMATM.Aminoglutethimide for example can be with Its commercial form is administered, such as trade mark is ORIMETENTM。
Including aromatization enzyme inhibitor is particularly useful for treating hormone receptor as the present composition of anti-tumor form agent Positive breast tumors.
The term as used herein " antiestrogenic " is related to the compound of the antagonising oestrogen effect on Estrogen Receptor. The term includes but not limited to tamoxifen, fulvestrant, Raloxifene and RALOXIFENE HCL.Tamoxifen for example may be used To be administered with its commercial form, such as trade mark is NOLVADEXTM.RALOXIFENE HCL can be for example administered with its commercial form, Such as trade mark is EVISTATM.Fulvestrant can be prepared as described in US4659516, such as can be with its commercial form Administration, such as trade mark are FASLODEXTM。
The term as used herein " topoisomerase I inhibitor " includes but not limited to topotecan, Irinotecan, 9- nitros Camptothecin conjugate PNU-166148 (the compound A1 in WO99/17804).Irinotecan can for example be given with its commercial form Medicine, such as trade mark are CAMPTOSARTM.Topotecan can be for example administered with its commercial form, such as trade mark is HYCAMTINTM。
The term as used herein " Topoisomerase II inhibitors " includes but not limited to anthracyclines (antracycline) Adriamycin (including Liposomal formulation, such as CAELYXTM), epirubicin, idarubicin and Nai Mo ratio stars (nemorubin), anthracene Quinones mitoxantrone and Lip river element anthraquinone and podophillotoxines etoposide and Teniposide.Etoposide for example can the cities Yi Qi Sell form administration, such as trade mark ETOPOPHOSTM.Teniposide can be for example administered with its commercially available formula, such as trade mark is VM 26- BRISTOLTM.Adriamycin can be for example administered with its commercial form, such as trade mark is ADRIBLASTINTM.Idarubicin is for example It can be administered with its commercial form, such as trade mark is ZAVEDOSTM.Mitoxantrone can be for example administered with its commercial form, such as Trade mark is NOVANTRONTM。
Term " microtubule active agent " is related to microtubule stabilization agent, including but not limited to taxane taxol (paclitaxel) and Docetaxel (docetaxel), catharanthus alkaloid, such as vincaleukoblastinum, especially vinblastine sulfate, discodermolide , such as epothilone B and D (discodermolide) and Epothilones (epothilone).Docetaxel for example can be with it Commercial form is administered, such as trade mark is TAXOTERETM.Vinblastine sulfate can be administered with its commercial form, such as trade mark is VINBLASTIN R.P.TM.Vincristine sulphate can be for example administered with its commercial form, such as trade mark is FARMISTIONTM。 Discodermolide can for example be obtained as described in US 5010099.
The term as used herein " alkylating agent " includes but not limited to ring phosphamidon, ifosfamide and melphalan.Ring phosphinylidyne Amine can be for example administered with its commercial form, such as trade mark is CYCLOSTINTM.Ifosfamide for example can be with its commercially available shape Formula is administered, such as trade mark is HOLOXANTM。
Term " inhibitors of histone deacetylase " is related to inhibition of histone deacetylase and has antiproliferative activity Compound.This includes compound disclosed in WO 02/22577, especially N- hydroxyls -3- [[(2- hydroxyethyls) [2- (1H- indoles - 3- yls) ethyl]-amino] methyl] phenyl] -2E-2- acrylamides, N- hydroxyls -3- [[(2- hydroxyethyls) [2- (1H- indoles - 3- yls) ethyl]-amino] methyl] phenyl] -2E-2- acrylamides and its pharmaceutically acceptable salt.Especially include further pungent Two anilide hydroxamic acid (SAHA).
Term " farnesyl transferase inhibitor " is related to inhibiting farnesyl transferase and has the chemical combination of antiproliferative activity Object.
Term " cox 2 inhibitor " is related to inhibiting cyclooxygenase 2 type enzyme (COX-2) and has the chemical combination of antiproliferative activity Object, such as celecoxib (Celebrex), profenoxib (Vioxx) and Rumi drawing are examined former times (COX189).
Term " MMP inhibitor " is related to inhibiting matrix metalloproteinase (MMP) and has the compound of antiproliferative activity.
Term " mTOR inhibitors " is related to inhibiting mammal rapamycin target (mTOR) and has antiproliferative activity Compound, such as sirolimus (Rapamune), everolimus (CerticanTM), CCI-779 and ABT578.
Term " anti-tumor formative antimetabolite " include but not limited to 5 FU 5 fluorouracil, Tegafur, capecitabine, carat bend Shore, cytarabine, fludarabine phosphate, fluridine (fluorouridine), gemcitabine, Ismipur, hydroxycarbamide, first The salt of ammonia petrin, Edatrexate and this kind of compound, in addition there are ZD1694 (RALTITREXEDTM)、LY231514 (ALIMTATM)、LY264618(LOMOTREXOLTM) and OGT719.
The term as used herein " platinum compounds " includes but not limited to carboplatin, cis-platinum and oxaliplatin.Carboplatin for example can be with It is administered with its commercial form, such as trade mark is CARBOPLATTM.Oxaliplatin can be for example administered with its commercial form, such as quotient It is designated as ELOXATINTM。
The term as used herein " reducing the compound of protein kinase activity and further anti-angiogenic compounds " packet Include but be not limited to reduce following active compound, for example, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), C-Src, protein kinase C, platelet derived growth factor (PDGF), Bcr-Abl, c-Kit, FLT3, insulin-like growth factor I Receptor (IGF-IR) and cell cycle protein dependent kinase (CDK) have the function of being different from reducing protein kinase activity machine The anti-angiogenic compounds of reason.
It reduces VEGF active compounds and especially inhibits vegf receptor, the especially tyrosine kinase activity of vegf receptor Compound and the compound combined with VEGF, especially general and specific those disclosed compound, albumen in the following documents Matter and monoclonal antibody：WQ98/35958 (description compound of formula I), WO00/09495, WO00/27820, WO00/59509, WO98/11223, WO00/27819, WO01/55114, WO01/58899 and EP0769947；M.Prewett et al. is in Cancer In Research 59 (1999) 5209-5218, Z.Zhu et al. in Cancer Res.58,1998,3209-3214 and J.Mordenti et al. is in Toxicologic Pathology, vol.27, those of described in no.1,14-21,1999； WO00/37502 and WO94/10202；AngiostatinTM, such as M.S.O ' Reilly et al., Cell 79,1994,315-328 institute It states.
Reduce the active compounds of EGF especially inhibits EGF combination compound, especially in the following documents generally with Those specifically disclosed compounds：WO97/02266 (description formula IV compound), EP0564409, WO99/03854, EP0520722、EP0566226、EP0787722、EP0837063、WO98/10767、WO97/30034、WO97/49688、 WOWO97/38983 and especially WO96/33980.
It includes but not limited to inhibition c-Src protein tyrosine kinases as defined below to reduce the active compounds of c-Src Those of active compound and SH2 interaction inhibitors, such as be disclosed in WO97/07131 and WO97/08193.
It includes but not limited to belong to the chemical combination of having structure type to inhibit the compound of c-Src protein tyrosine kinase activities Object：Pyrrolopyrimidine, especially pyrrolo- [2,3-d] pyrimidine；Purines；Pyrazolopyrimidines type, especially pyrrolo- [3,4-d] are phonetic Pyridine；Pyrazolopyrimidines type, especially pyrazolo pyrrolo- [3,4-d] pyrimidine and Pyridopyrimidine class, especially pyrido pyrrolo- [2, 3-d] pyrimidine.Preferably, which is related to being disclosed in WO96/10028, WO97/28161, WO97/32879 and WO97/49706 In those of compound.
It reduces the active compounds of IGF-IR and those of is especially disclosed in WO02/92599 compound.
It reduces protein kinase activity and the further particular compound that can also be used in combination with the compounds of this invention has Imatinib(Gleevec/Glivec)、PKC412、IressacTM(ZD1839), AEE788 and its pharmaceutically acceptable salt be (see also WO03/13541), PTK787 and its pharmaceutically acceptable salt (see also WO98/35958), ZD6474, GW2016, CHIR- 200131, CEP-7055/CEP-5214, CP-547632, KRN-633 and SU5416.
Anti-angiogenic compounds with the mechanism of action different from reducing protein kinase activity include but not limited to example Such as Thalidomide (THALOMID), celecoxib (Celebrex) and ZD6126.
The term as used herein " GnRF agonist " include but not limited to abarelix, Coserelin and Goserelin acetate.Coserelin is disclosed in US4100274, such as can be administered with its commercial form, such as trade mark is ZOLADEXTM.Abarelix can for example be prepared as described in US5843901.
The term as used herein " antiandrogen " includes but not limited to Bicalutamide (CASODEXTM), it for example can be as It is prepared described in US4636505.
Term " bengamide " is related to bengamide and its derivative with anti proliferative properties.
The term as used herein " bis-phosphonic acids compounds " include but not limited to according to bent phosphonic acids (pamidronic acid), Alendronic acid (alendronic acid).It can be for example administered with its commercial form according to bent phosphonic acids, such as trade mark is DIDRINELTM.Clodronate can be for example administered with its commercial form, such as trade mark is BONEFOSTM.Tiludronic Acid for example can be with It is administered with its commercial form, such as trade mark is SKELIDTM.Pamidronic acid can be for example administered with its commercial form, such as trade mark For AREDIATM.Alendronic acid can be for example administered with its commercial form, such as trade mark is FOSAMAXTM.Ibandronic acid for example may be used To be administered with its commercial form, such as trade mark is BONDRANATTM.Risedronic Acid can be for example administered with its commercial form, such as Trade mark is ACTONELTM.Zoledronic acid can be for example administered with its commercial form, such as trade mark is ZOMETATM。
Term " steroids " includes hydrocortisone, dexamethasone (Decadron), hydrogenated methyl Bo Nisonglong and Bo Ni Song Long.
The term as used herein " anti proliferative antibody " includes but not limited to Herceptin (Trastuzumab) (HerceptinTM), Herceptin-DM1, erlotinib (TercevaTM)、bevacizumab(AvastinTM), the appropriate uncommon agate of profit (Rituxan), PRO64553 (anti-CD 40) and 2C4 antibody.
For the treatment of acute casual leukaemia AML, formula (I), (II), (III) or (IV) compound can be with standard Leukemia therapy is used in combination, particularly for treating the therapy of AML.Specifically, formula (I), (II), (III) or (IV) chemical combination Object can be used for treating with such as farnesyl transferase inhibitor and/or other administered in combination of AML, such as soft red mould Element, adriamycin, Ara-C, VP-16, Teniposide, mitoxantrone, idarubicin, carboplatin and PKC412.
The structure of active constituent determined by code, adopted name or trade name can come from classic " Merck The current edition of index " comes from database, such as Patents International (such as IMS World Publications)。
The above-mentioned compound that can be used in combination with formula (I), (II), (III) or (IV) compound can be such as this field example It prepares and is administered described in document as referenced above.
In embodiments of the present invention, when being treated to patient according to the present invention, the amount of given drug depends on Factors, such as specific dosage regimen, disease or implant treatment and its seriousness, subject in need for the treatment of or host Unique (such as weight), still, according to specific ambient conditions, including for example used specific drug, administration route, control The illness for the treatment of and the subject or host for the treatment of, administration dosage can routinely be determined by methods known in the art.In general, For the dosage that adult treatment uses, administration dosage is typically at 0.02-5000mg/ days, for example, about 1-1500mg/ days models It encloses.The required dosage can easily be expressed as (or in a short time) one or be administered simultaneously or at interval appropriate Divided dose, such as daily two, three, four doses or more divided agent.It will be appreciated by persons skilled in the art that although giving Dosage range is stated, but specific effective quantity can suitably be adjusted according to the case where patient and in conjunction with doctor diagnosed.
The preparation of compound
Using Standard synthetic techniques well known by persons skilled in the art or using methods known in the art be described herein Method combination, formula (I), the compound of (II), (III) or (IV) can be synthesized.In addition, solvent given herein, temperature and Other reaction conditions can change according to art technology.
In some embodiments, it provided herein is the preparation method of kinase inhibitor compounds described herein and its Application method.In some embodiments, compound described herein can use the scheme of following synthesis to synthesize.It can use Compound is synthesized by using selectable starting material appropriate with following similar methods.
Starting material for synthesizing compound described herein can be synthesized or can be obtained from commercial source.Herein The compound of description can use technology well known by persons skilled in the art to other related compounds with different substituents And Material synthesis.The reaction for preparing compound disclosed herein can be by the reagent be deemed appropriate by those skilled in the art It is changed with condition, to be incorporated herein the various parts in the molecule of offer.
If desired, reaction product can use routine techniques to detach and purify, including but not limited to filters, distills, knot The methods of brilliant, chromatography.These products can be characterized using conventional method, including physical constant and spectrum data.
Using synthetic method described herein, compound disclosed herein is obtained with good yield and purity.According to herein Compound prepared by disclosed method is purified by conventional method known in the art, such as filtering, recrystallization, chromatography, distillation And combinations thereof.
Formula (I), the compound of (II), (III) or (IV) aromatic moiety on site, may be easy to occur various Metabolic response, therefore substituent group appropriate is introduced on aromatic ring structure, for example, only for example, halogen can restore, subtract Small or this metabolic pathway of elimination.
Embodiment
Non-limiting embodiment in detail below is to be interpreted as being merely illustrative, not limit in any way originally It is open.Although without being described in further detail, it is believed that those skilled in the art can be based on description herein, completely profit Use the disclosure.
Embodiment compound is referring to table 1.Prepare formula (II) compound synthetic schemes non-limiting embodiment referring to Scheme I.The non-limiting embodiment of the synthetic schemes of the compound of formula (III) is prepared referring to scheme II.Prepare the change of formula (IV) The non-limiting embodiment of the synthetic schemes of object is closed referring to scheme III.
1 embodiment compound structure of table
Scheme I
Embodiment 1
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (ring Propyl) methanone compounds 1 synthesis
As depicted in schemei, using a synthesize b, wherein a can by methods known in the art prepare or it is commercially available.In a When synthesizing b, with (S)-N- tertbutyloxycarbonyl -3- piperidine alcohols, the intermediate b of R configurations is obtained.Intermediate b (0.1g) 4N HCl Dioxane solution (1ml) processing, be stirred at room temperature 1 hour, be then concentrated to dryness product 0.08g, be dissolved in 4ml dichloromethane In, diisopropylethylamine (0.2mL), cyclopropanecarboxylic acid (0.03g), 2- (7- azos benzotriazole)-N, N, N' are sequentially added, N'- tetramethylurea hexafluorophosphoric acid ester HATU (0.15g) are stirred at room temperature 30 minutes, rear that the dilution of 20ml dichloromethane is added, successively With water, saturated common salt water washing, through anhydrous Na2SO4Dry, filtering, vacuum is spin-dried for.Residue is purified through column chromatography, obtains chemical combination Object 1 (0.03g), Exact Mass (calculated value):454.21；MS(ESI)m/z(M+1)+:455.22。
Embodiment 2
(R) -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) - The synthesis of 2,2,2- trifluoroethane ketone compound 2
The step of synthesis of compound 2 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):482.17；MS(ESI)m/z(M+1)+:483.1722。
Embodiment 3
(R) -3- (4- Phenoxyphenyls) -1- (1- ((trifluoromethyl) sulfonyl) piperidines -3- bases) -1H- pyrazolos [3,4- D] pyrimidine -4- amine compounds 3 synthesis
The step of synthesis of compound 3 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):518.13；MS(ESI)m/z(M+1)+:519.1315。
Embodiment 4
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- sulfonamide The synthesis of compound 4
The step of synthesis of compound 4 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):465.16；MS(ESI)m/z(M+1)+:466.1615。
Embodiment 5
(R) -2- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) - The synthesis of 2- oxalamide compounds 5
The step of synthesis of compound 5 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):457.19；MS(ESI)m/z(M+1)+:458.1915。
Embodiment 6
(S) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- (1H- imidazol-4 yls) propyl- 1- ketone compounds 6 synthesis
The step of synthesis of compound 6 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):523.24；MS(ESI)m/z(M+1)+:524.2413。
Embodiment 7
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- (1H- imidazol-4 yls) propyl- 1- ketone compounds 7 synthesis
The step of synthesis of compound 7 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):523.23；MS(ESI)m/z(M+1)+:524.2314。
Embodiment 8
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- (1H- indol-3-yls) propyl- 1- ketone compounds 8 synthesis
The step of synthesis of compound 8 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):572.26；MS(ESI)m/z(M+1)+:573.2615。
Embodiment 9
(S) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- (1H- indol-3-yls) propyl- 1- ketone compounds 9 synthesis
The step of synthesis of compound 9 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):572.26；MS(ESI)m/z(M+1)+:573.2614。
Embodiment 10
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- (4- hydroxy phenyls) propyl- 1- ketone compounds 10 synthesis
The step of synthesis of compound 10 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):549.25；MS(ESI)m/z(M+1)+:550.2514。
Embodiment 11
(S) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- (4- hydroxy phenyls) propyl- 1- ketone compounds 11 synthesis
The step of synthesis of compound 11 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):549.25；MS(ESI)m/z(M+1)+:550.2516。
Embodiment 12
(S) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) the amyl- 1- ketone compounds of -4- methyl 12 synthesis
The step of synthesis of compound 12 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):499.27；MS(ESI)m/z(M+1)+:500.2716。
Embodiment 13
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (pyrrole Pyridine -3- bases) methanone compounds 13 synthesis
The step of synthesis of compound 13 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):491.21；MS(ESI)m/z(M+1)+:492.2121。
Embodiment 14
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (piperazine Piperazine -1- bases) methanone compounds 14 synthesis
The step of synthesis of compound 14 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):498.58；MS(ESI)m/z(M+1)+:499.5821。
Embodiment 15
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) is (phonetic Pyridine -5- bases) methanone compounds 15 synthesis
The step of synthesis of compound 15 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):492.20；MS(ESI)m/z(M+1)+:493.2021。
Embodiment 16
(R) -4- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- carbonyls Base) methyl benzoate compound 16 synthesis
The step of synthesis of compound 16 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):548.22；MS(ESI)m/z(M+1)+:549.2221。
Embodiment 17
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (6- Aminopyridine -3- bases) methanone compounds 17 synthesis
The step of synthesis of compound 17 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):506.22；MS(ESI)m/z(M+1)+:507.2221。
Embodiment 18
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -3, The synthesis of 4- methylene-dioxies benzophenone compound 18
The step of synthesis of compound 18 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):534.20；MS(ESI)m/z(M+1)+:535.2021。
Embodiment 19
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -4- The synthesis of piperidines methanone compounds 19
The step of synthesis of compound 19 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):497.25；MS(ESI)m/z(M+1)+:498.2521。
Embodiment 20
(R) -3- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) - The synthesis of 3 propionitrile ketone compounds 20
The step of synthesis of compound 20 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):453.19；MS(ESI)m/z(M+1)+:454.1922。
Embodiment 21
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (2- Aminopyrimidine -5- bases) methanone compounds 21 synthesis
The step of synthesis of compound 21 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):507.21；MS(ESI)m/z(M+1)+:508.2134。
Embodiment 22
(R) -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) - The synthesis of 2- (dimethylamino) ethanone compounds 22
The step of synthesis of compound 22 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):471.24；MS(ESI)m/z(M+1)+:472.2431。
Embodiment 23
1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) - The synthesis of 2- hydroxyl propyl- 1- ketone compounds 23
The step of synthesis of compound 23 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):458.21；MS(ESI)m/z(M+1)+:458.2124。
Embodiment 24
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) propyl- 1 ketone compound 24 synthesis
The step of synthesis of compound 24 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):457.22；MS(ESI)m/z(M+1)+:458.2234。
Embodiment 25
(2R, 3R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidines - 1- yls) piperidin-1-yl) the amyl- 1- ketone compounds of -3- methyl 25 synthesis
The step of synthesis of compound 25 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):499.27；MS(ESI)m/z(M+1)+:500.2731。
Embodiment 26
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- phenyl propyl- 1- ketone compounds 26 synthesis
The step of synthesis of compound 26 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):533.25；MS(ESI)m/z(M+1)+:534.2541。
Embodiment 27
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) the amyl- 1- ketone compounds of -4- methyl 27 synthesis
The step of synthesis of compound 27 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):499.27；MS(ESI)m/z(M+1)+:500.2733。
Embodiment 28
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Pyrrolidin-1-yl) the amyl- 1- ketone compounds of -4- methyl 28 synthesis
The step of synthesis of compound 28 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):485.58；MS(ESI)m/z(M+1)+:486.5833。
Embodiment 29
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) is (different Oxazole -5- bases) methanone compounds 29 synthesis
The step of synthesis of compound 29 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):481.19；MS(ESI)m/z(M+1)+:482.1921。
Embodiment 30
(R) -1- (1- (methyl sulphonyl) piperidines -3- bases) -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] are phonetic The synthesis of pyridine -4- amine compounds 30
The step of synthesis of compound 30 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):464.16；MS(ESI)m/z(M+1)+:465.1622。
Embodiment 31
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of morpholine ethanone compounds 31
The step of synthesis of compound 31 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):513.25；MS(ESI)m/z(M+1)+:514.2531。
Embodiment 32
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (ring Amyl- 2- yls) ethanone compounds 32 synthesis
The step of synthesis of compound 32 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):496.26；MS(ESI)m/z(M+1)+:496.2631。
Embodiment 33
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (1- Methyl piperidine -4- bases) methanone compounds 33 synthesis
The step of synthesis of compound 33 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):511.27；MS(ESI)m/z(M+1)+:512.2731。
Embodiment 34
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) ethyl ketone The synthesis of compound 34
The step of synthesis of compound 34 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):428.20；MS(ESI)m/z(M+1)+:429.2031。
Embodiment 35
(R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (4- ((4- methylpiperazine-1-yls) methyl) phenyl) methanone compounds 35 synthesis
The step of synthesis of compound 35 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):602.31；MS(ESI)m/z(M+1)+:602.3123。
Embodiment 36
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -3- The synthesis of chlroacetone compound 36
The step of synthesis of compound 36 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):476.17；MS(ESI)m/z(M+1)+:477.1723。
Embodiment 37
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of bromacetone compound 37
The step of synthesis of compound 37 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):520.12；MS(ESI)m/z(M+1)+:522.1217。
Embodiment 38
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of chlroacetone compound 38
The step of synthesis of compound 38 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):476.17；MS(ESI)m/z(M+1)+:477.1725。
Embodiment 39
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of (4- methylpiperazine-1-yls) ethanone compounds 39
The step of synthesis of compound 39 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):526.28；MS(ESI)m/z(M+1)+:527.2826。
Embodiment 40
(R) -3- (4- Phenoxyphenyls) -1- (1- (the third sulfo group) piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- The synthesis of amine compounds 40
The step of synthesis of compound 40 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):492.19；MS(ESI)m/z(M+1)+:493.1921。
Embodiment 41
(R) -3- (4- Phenoxyphenyls) -1- (1- (second sulfo group) piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- The synthesis of amine compounds 41
The step of synthesis of compound 41 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):478.18；MS(ESI)m/z(M+1)+:479.1821。
Embodiment 42
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) trichlorine The synthesis of ethanone compounds 42
The step of synthesis of compound 42 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):478.18；MS(ESI)m/z(M+1)+:479.1821。
Embodiment 43
(R) -2- amino -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) ethanone compounds 43 synthesis
The step of synthesis of compound 43 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):443.21；MS(ESI)m/z(M+1)+:444.2118。
Embodiment 44
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3-Hydroxybutanone compound 44 synthesis
The step of synthesis of compound 44 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):487.23；MS(ESI)m/z(M+1)+:488.2321。
Embodiment 45
(R) -2- amino -1- ((R) 3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -3- espeletons compound 45 synthesis
The step of synthesis of compound 45 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):485.25；MS(ESI)m/z(M+1)+:486.2531。
Embodiment 46
(R) -3- amino -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) acetonide 46 synthesis
The step of synthesis of compound 46 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):457.22；MS(ESI)m/z(M+1)+:457.2221。
Embodiment 47
(R) -2- amino -1- ((R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidin-1-yl) acetonide 47 synthesis
The step of synthesis of compound 47 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):457.22；MS(ESI)m/z(M+1)+:458.2226。
Embodiment 48
(R) -2- amino -1- ((R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- Base) piperidin-1-yl) -3- hydroxypropanone-s compound 48 synthesis
The step of synthesis of compound 48 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):473.22；MS(ESI)m/z(M+1)+:474.2225。
Embodiment 49
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -3, The synthesis of 3- dimethyl butyrates ketone compound 49
The step of synthesis of compound 49 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):473.22；MS(ESI)m/z(M+1)+:474.2225。
Embodiment 50
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2, The synthesis of 2- dimethyl butyrates ketone compound 50
The step of synthesis of compound 50 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):473.22；MS(ESI)m/z(M+1)+:474.2226。
Embodiment 51
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -3, The synthesis of 3,3- trifluoroacetones compound 51
The step of synthesis of compound 51 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):496.18；MS(ESI)m/z(M+1)+:497.1824。
Embodiment 52
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of cyclopropyl ethanone compounds 52
The step of synthesis of compound 52 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):468.23；MS(ESI)m/z(M+1)+:469.2327。
Embodiment 53
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -3- The synthesis of espeleton compound 53
The step of synthesis of compound 53 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):470.24；MS(ESI)m/z(M+1)+:471.2427。
Embodiment 54
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) butanone The synthesis of compound 54
The step of synthesis of compound 54 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):456.23；MS(ESI)m/z(M+1)+:457.2327。
Embodiment 55
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2, The synthesis of 2- dimethyl propylenes ketone compound 55
The step of synthesis of compound 55 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):470.24；MS(ESI)m/z(M+1)+:471.2426。
Embodiment 56
(S) -4- amino -5- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -5- carbonyl valeryls amine compounds 56 synthesis
The step of synthesis of compound 56 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):514.24；MS(ESI)m/z(M+1)+:515.2428。
Embodiment 57
(R) -4- amino -5- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) -5- carbonyl valeryls amine compounds 57 synthesis
The step of synthesis of compound 57 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):514.24；MS(ESI)m/z(M+1)+:515.2427。
Embodiment 58
(R) -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) - The synthesis of 3- (4- methylpiperazine-1-yls) acetonide 58
The step of synthesis of compound 58 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):540.31；MS(ESI)m/z(M+1)+:541.3135。
Embodiment 59
(R)-(2- (3- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- Base) -2- carbonyls) ethylcarbamate 59 synthesis
The step of synthesis of compound 59 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):543.26；MS(ESI)m/z(M+1)+:544.2627。
Embodiment 60
(R) -4- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- carbonyls Base) piperidines -1- methyl formates compound 60 synthesis
The step of synthesis of compound 60 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):555.26；MS(ESI)m/z(M+1)+:556.2627。
Embodiment 61
(R) -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- Base) the amyl- 1- ketone compounds of -2- hydroxy-4-methyls 61 synthesis
The step of synthesis of compound 61 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):500.25；MS(ESI)m/z(M+1)+:501.2527。
Embodiment 62
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -5- The synthesis of amino pentanone compound 62
The step of synthesis of compound 62 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):485.25；MS(ESI)m/z(M+1)+:486.2526。
Embodiment 63
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of hydroxyl hex- 1- ketone compounds 63
The step of synthesis of compound 63 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):500.25；MS(ESI)m/z(M+1)+:501.2528。
Embodiment 64
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) pyrrolidin-1-yl) - The synthesis of 2- amino ethanone compounds 64
The step of synthesis of compound 64 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):429.19；MS(ESI)m/z(M+1)+:430.1928。
Embodiment 65
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) pyrrolidin-1-yl) - The synthesis of 2- (dimethylamino) ethanone compounds 65
The step of synthesis of compound 65 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):457.22；MS(ESI)m/z(M+1)+:458.2225。
Embodiment 66
(R)-(2- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) pyrrolidines -1- Base) -2- carbonyls) ethylcarbamate compound 66 synthesis
The step of synthesis of compound 66 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):529.24；MS(ESI)m/z(M+1)+:530.2427。
Embodiment 67
(R) -1- (1- (methyl sulphonyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] are phonetic The synthesis of pyridine -4- amine compounds 67
The step of synthesis of compound 67 is by using similar to described in embodiment 1 is completed.Exact Mass (are calculated Value):450.15；MS(ESI)m/z(M+1)+:451.1527。
Embodiment 68
(4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (1- methyl Piperidin-4-yl) methanone compounds 68 synthesis
Scheme II
As illustrated in scheme ii, the synthesis of compound 68 synthesizes c by using similar to the method described in embodiment 1 by a, Raw material is only replaced with into N- tertbutyloxycarbonyl -4- piperidine alcohols by (S)-N- tertbutyloxycarbonyl -3- piperidine alcohols.By compound c It is dissolved in dichloromethane, trifluoroacetic acid is added, is stirred at room temperature 2 hours, rear to concentrate, ethyl acetate and water-soluble carbon is added in residue Sour potassium, organic phase drying, filtering and concentrating are added with stirring Isosorbide-5-Nitrae-dioxane solution of 4.0M HCl, and solid is collected and uses second Acetoacetic ester is washed, and rear solid is dissolved in the solution of ethyl acetate and potassium carbonate, and organic phase drying is concentrated to give intermediate d.By compound d (20mg, 0.05mmol) is dissolved in n,N-Dimethylformamide (2ml), addition 1- methyl piperidine -4- formic acid (7.4mg, 0.05mmol), diisopropyl ethyl amine (7.4mg, 0.05mmol), HATU (21.6mg, 0.05mmol), mixture stirs at room temperature It mixes 0.5 hour, afterwards plus ethyl acetate dilution, washing, drying, concentration column chromatography obtain 12mg compound as white solid 68.Exact Mass (calculated value):511.62；MS(ESI)m/z(M+1)+:512.6227。
Embodiment 69
1- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of (4- methylpiperazine-1-yls) ethanone compounds 69
The step of synthesis of compound 69 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value):526.63；MS(ESI)m/z(M+1)+:527.6329。
Embodiment 70
1- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of quinoline ethanone compounds 70
The step of synthesis of compound 70 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value):513.59；MS(ESI)m/z(M+1)+:514.5917。
Embodiment 71
(4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) (4- ((4- Methylpiperazine-1-yl) methyl) phenyl) and methanone compounds 71 synthesis
The step of synthesis of compound 71 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value):602.73；MS(ESI)m/z(M+1)+:603.7325。
Embodiment 72
1- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of (dimethylamino) ethanone compounds 72
The step of synthesis of compound 72 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value):471.55；MS(ESI)m/z(M+1)+:472.5532。
Embodiment 73
1- (1- (methyl sulphonyl) piperidin-4-yl) -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidines -4- The synthesis of amine compounds 73
The step of synthesis of compound 73 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value):464.54；MS(ESI)m/z(M+1)+:465.5423。
Embodiment 74
(R) -2- amino -1- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) -4- methylpentane -1- ketone compounds 74 synthesis
The step of synthesis of compound 74 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value):499.61；MS(ESI)m/z(M+1)+:500.6128。
Embodiment 75
1- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- The synthesis of (methylamino) ethanone compounds 75
The step of synthesis of compound 75 is by using similar to described in embodiment 68 is completed.Exact Mass (are calculated Value):457.53；MS(ESI)m/z(M+1)+:458.5316。
Embodiment 76
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (two Methylamino) acetamide compound 76 synthesis
Scheme III
As illustrated in scheme ii, the synthesis of compound 76 synthesizes e by using similar to the method described in embodiment 1 by a, Raw material is only replaced with into N-Boc-4- aminocyclohexanols by (S)-N- tertbutyloxycarbonyl -3- piperidine alcohols.Compound e is dissolved in In dichloromethane, trifluoroacetic acid is added, is stirred at room temperature 2 hours, rear to concentrate, ethyl acetate and water-soluble carbonic acid is added in residue Potassium, organic phase drying, filtering and concentrating are added with stirring Isosorbide-5-Nitrae-dioxane solution of 4.0M HCl, and solid is collected and uses acetic acid Ethyl ester is washed, and rear solid is dissolved in the solution of ethyl acetate and potassium carbonate, and organic phase drying is concentrated to give intermediate f.By compound f (20mg, 0.05mmol) is dissolved in n,N-Dimethylformamide (2ml), addition 2- (dimethylamino) acetic acid (5.1mg, 0.05mmol), diisopropyl ethyl amine (7.4mg, 0.05mmol), HATU (21.6mg, 0.05mmol), mixture stirs at room temperature It mixes 0.5 hour, afterwards plus ethyl acetate dilution, washing, drying, concentration column chromatography obtain 16mg compound as white solid 76.Exact Mass (calculated value):485.58；MS(ESI)m/z(M+1)+:486.5816。
Embodiment 77
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) rings Hexyl) -4- methylpentanamides hydrochloride compound 77 synthesis
The step of synthesis of compound 77 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.64；MS(ESI)m/z(M+1)+:514.6423。
Embodiment 78
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) methyl sulphur The synthesis of amide compound 78
The step of synthesis of compound 78 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):478.57；MS(ESI)m/z(M+1)+:479.5717。
Embodiment 79
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (first Base amino) acetamide compound 79 synthesis
The step of synthesis of compound 79 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):471.55；MS(ESI)m/z(M+1)+:472.5521。
Embodiment 80
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -1- first The synthesis of base amino piperidine -4- benzamide compounds 80
The step of synthesis of compound 80 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):525.64；MS(ESI)m/z(M+1)+:526.6422。
Embodiment 81
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (4- Methylpiperazine-1-yl) acetamide compound 81 synthesis
The step of synthesis of compound 81 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):540.66；MS(ESI)m/z(M+1)+:541.6625。
Embodiment 82
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of quinoline acetamide compound 82
The step of synthesis of compound 82 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):527.62；MS(ESI)m/z(M+1)+:528.6223。
Embodiment 83
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- cyanogen The synthesis of yl acetamide compound 83
The step of synthesis of compound 83 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):467.52；MS(ESI)m/z(M+1)+:468.5218。
Embodiment 84
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -4- methylpentanamides hydrochloride compound 84 synthesis
The step of synthesis of compound 84 is by using similar to described in embodiment 76 is completed, only by raw material by N- Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):513.64；MS(ESI)m/ z(M+1)+:514.6424。
Embodiment 85
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -4- methylpentanamides hydrochloride compound 85 synthesis
The step of synthesis of compound 85 is by using similar to described in embodiment 76 is completed, only by raw material by N- Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):513.64；MS(ESI)m/ z(M+1)+:514.6425。
Embodiment 86
(R) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base) -3- metlzylbutanamide Hydroclalorides compound 86 synthesis
The step of synthesis of compound 86 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):499.61；MS(ESI)m/z(M+1)+:500.2785。
Embodiment 87
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -3- The synthesis of methyl -2- (methylamino) butanamide hydrochloride 87
The step of synthesis of compound 87 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.63；MS(ESI)m/z(M+1)+:514.2985。
Embodiment 88
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino) -3- methylbutyryls amine compounds 88
The step of synthesis of compound 88 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):527.66；MS(ESI)m/z(M+1)+:528.3065。
Embodiment 89
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base) -3- metlzylbutanamide Hydroclalorides compound 89 synthesis
The step of synthesis of compound 89 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):499.61；MS(ESI)m/z(M+1)+:500.2787.
Embodiment 90
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -3- The synthesis of methyl -2- (methylamino) butanamide hydrochloride 90
The step of synthesis of compound 90 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.63；MS(ESI)m/z(M+1)+:514.2986。
Embodiment 91
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino) -3- methylbutyryls amine compounds 91
The step of synthesis of compound 91 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):527.66；MS(ESI)m/z(M+1)+:528.3067。
Embodiment 92
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -4- The synthesis of methyl -2- (methylamino) valeryls amine hydrochlorate 92
The step of synthesis of compound 92 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):527.66；MS(ESI)m/z(M+1)+:528.3063。
Embodiment 93
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino) -4- methylpentanamides 93
The step of synthesis of compound 93 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):541.69；MS(ESI)m/z(M+1)+:542.3263。
Embodiment 94
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base) -4- methylpentanamides 94 synthesis
The step of synthesis of compound 94 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.63；MS(ESI)m/z(M+1)+:514.2963。
Embodiment 95
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -4- The synthesis of methyl -2- (methylamino) valeryls amine hydrochlorate 95
The step of synthesis of compound 95 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):527.66；MS(ESI)m/z(M+1)+:528.3065。
Embodiment 96
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino) -4- methylpentanamides 96
The step of synthesis of compound 96 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):541.69；MS(ESI)m/z(M+1)+:542.3266。
Embodiment 97
(R) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base)-butanamide hydrochloride compound 97 synthesis
The step of synthesis of compound 97 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):485.58；MS(ESI)m/z(M+1)+:486.2666。
Embodiment 98
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (methylamino)-butanamide hydrochloride 98
The step of synthesis of compound 98 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):499.61；MS(ESI)m/z(M+1)+:500.2766。
Embodiment 99
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino) butyramide compounds 99
The step of synthesis of compound 99 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.63；MS(ESI)m/z(M+1)+:514.2966。
Embodiment 100
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base)-butanamide hydrochloride compound 100 synthesis
The step of synthesis of compound 100 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):485.58；MS(ESI)m/z(M+1)+:486.2669。
Embodiment 101
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (methylamino) butanamide hydrochloride 101
The step of synthesis of compound 101 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):499.61；MS(ESI)m/z(M+1)+:500.2769。
Embodiment 102
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino) butyramide compounds 102
The step of synthesis of compound 102 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.63；MS(ESI)m/z(M+1)+:514.2963。
Embodiment 103
(R) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base)-pentanamide hydrochloride compound 103 synthesis
The step of synthesis of compound 103 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):499.61；MS(ESI)m/z(M+1)+:500.2763。
Embodiment 104
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (methylamino)-valeryl amine hydrochlorate 104
The step of synthesis of compound 104 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.63；MS(ESI)m/z(M+1)+:514.2963。
Embodiment 105
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino)-pentanamide 105
The step of synthesis of compound 105 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):527.66；MS(ESI)m/z(M+1)+:528.3063。
Embodiment 106
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base)-pentanamide hydrochloride compound 106 synthesis
The step of synthesis of compound 106 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):499.61；MS(ESI)m/z(M+1)+:500.2769。
Embodiment 107
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (methylamino)-valeryl amine hydrochlorate 107
The step of synthesis of compound 107 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):513.63；MS(ESI)m/z(M+1)+:514.2971。
Embodiment 108
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- The synthesis of (dimethylamino)-pentanamide 108
The step of synthesis of compound 108 is by using similar to described in embodiment 76 is completed.Exact Mass (are calculated Value):527.66；MS(ESI)m/z(M+1)+:528.3068。
Embodiment 109
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -4- methyl -2- (methylamino) pentanamides hydrochloride compound 109 synthesis
The step of synthesis of compound 109 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):527.66；MS(ESI) m/z(M+1)+:528.3074。
Embodiment 110
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -4- methyl -2- (dimethylamino) valeryls amine compounds 110 synthesis
The step of synthesis of compound 110 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):541.69；MS(ESI) m/z(M+1)+:542.3274。
Embodiment 111
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -4- methylpentanamides hydrochloride compound 111 synthesis
The step of synthesis of compound 111 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):513.63；MS(ESI) m/z(M+1)+:514.2974。
Embodiment 112
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -4- methyl -2- (methylamino) pentanamides hydrochloride compound 112 synthesis
The step of synthesis of compound 112 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):527.66；MS(ESI) m/z(M+1)+:528.3074。
Embodiment 113
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -4- methyl -2- (dimethylamino) valeryls amine compounds 113 synthesis
The step of synthesis of compound 113 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):541.69；MS(ESI) m/z(M+1)+:542.3277。
Embodiment 114
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -4- methylpentanamides hydrochloride compound 114 synthesis
The step of synthesis of compound 114 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):513.63；MS(ESI) m/z(M+1)+:514.2976。
Embodiment 115
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -4- methyl -2- (methylamino) pentanamides hydrochloride compound 115 synthesis
The step of synthesis of compound 115 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):527.66；MS(ESI) m/z(M+1)+:528.3077。
Embodiment 116
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -4- methyl -2- (dimethylamino) valeryls amine compounds 116 synthesis
The step of synthesis of compound 116 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):541.69；MS(ESI) m/z(M+1)+:542.3280。
Embodiment 117
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -4- methyl -2- (methylamino) pentanamides hydrochloride compound 117 synthesis
The step of synthesis of compound 117 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):527.66；MS(ESI) m/z(M+1)+:528.3082。
Embodiment 118
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -4- methyl -2- (dimethylamino) pentanamide compound 118 synthesis
The step of synthesis of compound 118 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):541.69；MS(ESI) m/z(M+1)+:542.3283。
Embodiment 119
(R) -2- amino-N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) acetamide hydrochloride 119
The step of synthesis of compound 119 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):580.68；MS(ESI) m/z(M+1)+:581.2983。
Embodiment 120
(R) -2- amino-N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) -2- (methylamino) acetamide hydrochloride 120
The step of synthesis of compound 120 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):594.71；MS(ESI) m/z(M+1)+:595.3183。
Embodiment 121
(R) -2- amino-N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Cis- 1,4- cyclohexyl) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) -2- (dimethylamino) acetamide 121
The step of synthesis of compound 121 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):608.73；MS(ESI) m/z(M+1)+:609.3383。
Embodiment 122
N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cis- 1,4- hexamethylenes Base) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) acetamide 122
The step of synthesis of compound 122 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with trans- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):565.67；MS(ESI) m/z(M+1)+:566.2883。
Embodiment 123
N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) trans- 1,4- hexamethylenes Base) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) acetamide 123
The step of synthesis of compound 123 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):565.67；MS(ESI) m/z(M+1)+:566.2886。
Embodiment 124
(S) -2- amino-N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) acetamide hydrochloride 124
The step of synthesis of compound 124 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):580.68；MS(ESI) m/z(M+1)+:581.2988。
Embodiment 125
(S) -2- amino-N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) -2- (methylamino) acetamide hydrochloride 125
The step of synthesis of compound 125 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):594.71；MS(ESI) m/z(M+1)+:595.3187。
Embodiment 126
(S) -2- amino-N- (4- (4- amino -3- (4- phenoxy phenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Trans- 1,4- cyclohexyl) -2- (synthesis of 5- (tertiary butyl) isoxazole -3-bases) -2- (dimethylamino) acetamide 126
The step of synthesis of compound 126 is by using similar to described in embodiment 76 is completed, only by raw material by N-Boc-4- aminocyclohexanols replace with cis- 4-Boc- aminocyclohexanols.Exact Mass (calculated value):608.73；MS(ESI) m/z(M+1)+:609.3390。
Embodiment 127：Influence to cancer cell multiplication
By testing influence (table 2) of the compound of the present invention to growth of cancer cells, compound pair during further assessment is literary The inhibiting effect of cancer cell multiplication, and its selectivity to inhibiting cancer cell multiplication.The acute monokaryon of people has been selected in the present embodiment Cell leukemia cell strain MV4-11 (expression FLT3/ITD mutated genes), human muscle creatine kinase cell strain MOLM- 13 (expression FLT3/ITD mutated genes and wild type FLT3 genes), human muscle creatine kinase cell strain MOLM-14 (expression FLT3/ITD mutated genes and wild type FLT3 genes), human muscle creatine kinase cell strain OCI-AML-3 (expression FLT3A680V mutated genes), human muscle creatine kinase cell strain U937 (expression wild type FLT3 genes), mouse original B it is thin Born of the same parents BaF3, the above cell are purchased from ATCC.Mouse TEL-BaF3-FLT3/ITD has also been selected (to stablize expression FLT3/ITD mutation Activated protein kinase), mouse TEL-BaF3-FLT3-D835Y (stablize expression FLT3D835Y mutation activated protein kinase), mouse TEL- BaF3-BMX (stablizing expression BMX kinases), mouse TEL-FLT3-BaF3 (stablizing expression FLT3 kinases), mouse BaF3-FLT3- ITD-D835Y (activated protein kinase for stablizing expression FLT3/ITD D835Y mutation), mouse BaF3-FLT3-ITD-F691L (stablize Express the activated protein kinase of FLT3/ITD F691L mutation), mouse TEL-cKIT-BaF3 (stablizing expression cKIT kinases), mouse BaF3-tel-cKit-N882K (activated protein kinase for stablizing expression cKIT N882K mutation), mouse BaF3-tel-cKit-D816V (activated protein kinase for stablizing expression cKIT D816V mutation), mouse BaF3-tel-cKit-T670I (stablize expression cKIT T670I The activated protein kinase of mutation), mouse TPR-MET-BaF3 (stablize expression MET kinases), mouse TEL-BaF3-EGFR (stablize expression EGFR kinases), mouse BaF3-FL-EGFR-L858R (activated protein kinase for stablizing expression EGFR L858R mutation), mouse TEL- BaF3-BLK (stablizing expression BLK kinases), mouse TEL-JAK1-BaF3 (stablizing expression JAK1 kinases).Above-mentioned cell strain by This laboratory is built, and construction method is：PCR expands the mankind FLT3/ITD, FLT3D835Y, BMX, FLT3, FLT3/ITD respectively D835Y、FLT3/ITD F691L、cKIT、cKIT N882K、cKIT D816V、cKIT T670I、MET、EGFR、EGFR L858R, BLK, JAK1 kinases region sequence, and it is inserted respectively into the MSCV-Puro carriers with N-terminal TEL or TPR segment (Clontech), by retrovirus method, stabilization is transferred to mouse BaF3 cells, and removes IL-3 growth factors, finally It obtains relying on FLT3/ITD, FLT3D835Y, BMX, FLT3, FLT3/ITD D835Y, FLT3/ITD F691L, cKIT, cKIT N882K, cKIT D816V, cKIT T670I, MET, EGFR, EGFR L858R, BLK, JAK1 are transferred to the cell line of albumen.
In embodiment by various concentration (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μ M, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM in DMSO) above compound be added separately to above-mentioned cell In, and be incubated 72 hours, use Cell(Promega, the U.S.) chemistry self-luminous method cell viability detection reagent Box detects number of viable cells by being quantitative determined to the ATP in living cells.Experimental result is shown in Table 2.
The influence of 2 cell proliferation of table
Continued 2
Continued 2
Embodiment 128：Compound 22, compound 77 and compound 84 are in cell to the shadow of FLT3 upstream and downstream signal paths It rings
In the human muscle creatine kinase cell MV4-11 (tables for carrying FLT3 genes and/or FLT3/ITD mutated genes Up to FLT3/ITD mutated genes) cell strain and human muscle creatine kinase cell strain MOLM-14 (expression FLT3/ITD saltant types Gene and wild type FLT3 genes) in cell strain, by measuring many cellular biochemistry terminals and functional terminal, test (AC220 is purchased from Hao Yuan by compound 22, compound 77, compound 84 and control compound FLT3 kinase inhibitors AC220 Chemexpress companies, Shanghai) to the phosphorylation of the FLT3 and/or FLT3/ITD protein kinases in cell and its closely related Signal path downstream STAT5 protein phosphorylations influence and other relevant Protein kinase ERKs, AKT phosphorylations influence, We also have detected the influence (Fig. 1) of PROTEIN C-Myc and transcription factor NF-KB subunit p65 phosphorylations simultaneously.It is dense with difference Degree 0 μM, 0.03 μM, 0.1 μM, 0.3 μM, the compound 22 of 1 μM, 3 μM (in DMSO), compound 77,0 μM of various concentration, 0.003 μM, 0.01 μM, 0.03 μM, 0.1 μM, the compound 84 of 0.3 μM, 1 μM (in DMSO) and 0.1 μM (in DMSO) FLT3 kinase inhibitors AC220 handles the acute myeloid leukemia cells in children MV 4- for carrying FLT3 and/or FLT3/ITD genes respectively 11, sample is collected in MOLM-14 cell strains 4 hours.Measure compound on intracellular in STAT5, C-Myc, ERK, NF- κ B p65, The influence (Fig. 1) of the protein phosphorylations such as AKT.
Experimental result is as shown in Figure 1：In MV 4-11 and MOLM-14 cell lines, compound 22, compound 77 and chemical combination Object 84 can consumingly inhibit the phosphorylation of protein kinase FLT3.In addition, in the urgency for carrying FLT3 and/or FLT3/ITD genes In property marrow leukaemia cell MV4-11 and MOLM-14 cell strain, compound 22, compound 77 and compound 84 are in cell The phosphorylation of the downstreams FLT3/ITD albumen STAT5 also has an inhibiting effect strongly, and pair close with FLT3 protein kinases Relevant PROTEIN C-Myc has particularly apparent degradation.In same experiment, control compound FLT3 kinase inhibitors AC220 can consumingly inhibit the protein kinase FLT3's and Protein S TAT5 closely related with FLT3/ITD and PROTEIN C-Myc Phosphorylation.It is compared by experimental result, we can also be seen that the compound of the present invention 77, compound 84 compare control compound FLT3 kinase inhibitor AC220 drug effects are more preferable.
Embodiment 128 shows that compound 22, compound 77, compound 84 can be strong inhibits protein kinase FLT3's Phosphorylation influences the phosphorylation of the signal path downstream albumen STAT5 of protein kinase FLT3 in cell, and then inhibits to carry FLT3 And/or the cell Proliferation of the acute myeloid leukemia cells in children strain of FLT3/ITD genes.
Embodiment 129：External inhibitory activity (enzyme activity) detection
In vitro compound 33, compound 30, compound 14, compound 20, compound 22, chemical combination are measured in enzyme activity experiment Object 23, compound 25, compound 26, compound 27, compound 5, compound 6, compound 7, compound 8, compound 9, chemical combination Object 10, compound 12, compound 2, compound 3, compound 4, compound 76, compound 77, compound 78, is changed compound 11 Object 48, compound 47, compound 45, compound 44, compound 43 and AC220 are closed to protein kinase FLT3, FLT3/ITD and BTK IC50 values.By in the intracellular section regional cloning to insect expression vector pAcG2T of protein kinase FLT3, FLT3/ITD and BTK, Utilize insect expression system BaculoGoldTMBaculovirus Expression System (BD Pharmingen) carry out egg White expression, and carry GST labels.The carrier built is transfected to SF9 packaging virus, albumen is expressed with virus infection SF9.
Take the 9 μ L of FLT3 and BTK protein kinases (6ng/ μ L) of purifying respectively with 1 μ L of the above compound of three times gradient dilution It reacts at room temperature 4 hours (final concentration of 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM of drug)；
2 μ L ATP and 3 μ L substrates Poly (4 are added:1Glu, Tyr) Peptide (Promega, the U.S.) (distinguish by final concentration For 10 μM and 0.2 μ g/ μ L), 37 DEG C are reacted 1 hour；
The kinase solution after 5 μ L reactions is taken, 5 μ L ADP-Glo are addedTM(Promega, the U.S.) reagent reacts at room temperature 40min To terminate kinase reaction and run out of remaining ATP；
10 μ L kinase assay reagents are added, ADP is converted to ATP, uses luciferase/luciferin reaction detection of coupling Newly synthesized ATP is mapped after being read using Envision, calculates IC50 values (table 3).
Experimental result is as shown in Figure 2：The above-mentioned example compound of the present invention swashs FLT3, FLT3/ITD and BTK albumen Enzyme has strong inhibiting effect.These results illustrate that the compounds of this invention is the inhibitor of FLT3 kinases, while to FLT3/ ITD and BTK kinases also has inhibiting effect.
Table 3 external inhibitory activity (enzyme activity) test result
Embodiment 130：Compound 22 and compound 84 are on cell to the influence of Apoptosis
In order to prove that the death of cell after medication is to carry FLT3 genes and/or FLT3/ by apoptosis or necrosis In acute myeloid leukemia cells in children MOLM-13, MV4-11 cell strain of ITD mutated genes, compound 22 and chemical combination are had detected Object 84 in cell couple poly- adenosine diphosphate of the DNA repair enzyme closely related with Apoptosis-ribose polymerase PARP, contain half Guang The influence of 3 protein cleavages of aspartic acid proteolytic enzyme Caspase of propylhomoserin.With 0 μM of various concentration, 0.03 μM, 0.1 μM, 22,0 μM of the compound of 0.3 μM, 1 μM (in DMSO), 0.03 μM, 0.1 μM, the compound 84 of 0.3 μM, 1 μM (in DMSO), The FLT3 kinase inhibitors AC220 of 0.1 μM (in DMSO) handles MOLM-13, MV 4-11 cell strains respectively, then exists respectively Cell is collected after 12 hours, 24 hours, 48 hours.The medicine of various concentration is detected in different time sections pair with Western Blot The poly- adenosine diphosphate of DNA repair enzymes-ribose polymerase PARP and aspartic acid proteolytic enzyme Caspase 3 containing cysteine Shear protein influence (Fig. 3).
Experimental result is as shown in Figure 3：For carrying the acute myelogenous white of FLT3 genes and/or FLT3/ITD mutated genes Blood disease cell line MOLM-13, when the Drug level of compound 22 is 0.1 μM, just it can be seen that very bright after acting on 12 hours The shearing of the poly- adenosine diphosphate of aobvious DNA repair enzymes-ribose polymerase PARP and the particularly apparent asparagus fern containing cysteine The shearing of propylhomoserin proteolytic enzyme Caspase 3；When the Drug level of compound 84 is 0.1 μM, effect can be seen after 24 hours To the poly- adenosine diphosphate of particularly apparent DNA repair enzymes-ribose polymerase PARP shearing and it is particularly apparent contain cysteine Aspartic acid proteolytic enzyme Caspase 3 shearing, be used in the same manner 0.1 μM of control compound FLT3 kinase inhibitors AC220 can also observe same phenomenon.For carrying the acute myelogenous white of FLT3 genes and/or FLT3/ITD mutated genes Blood disease cell MV 4-11, when the Drug level of compound 22 is 0.1 μM, after acting on 24 and 48 hours respectively, it can be seen that bright The shearing of the poly- adenosine diphosphate of aobvious DNA repair enzymes-ribose polymerase PARP, can also see the apparent day containing cysteine The shearing of winter propylhomoserin proteolytic enzyme Caspase 3.When the Drug level of compound 84 is 0.03 μM, after acting on 24 hours, energy The shearing for enough observing the more apparent poly- adenosine diphosphate of DNA repair enzymes-ribose polymerase PARP, can also see containing half Guang ammonia The shearing of the aspartic acid proteolytic enzyme Caspase 3 of acid.Embodiment 130, which demonstrates compound 22 and compound 84, to draw Act the apoptosis for the acute myeloid leukemia cells in children for carrying FLT3 genes and/or FLT3/ITD mutated genes.
Embodiment 131：The influence of compound 22 and compound 84 cell cycle on cell
In order to study which growth cycle cell after medication is stopped in, the acute of FLT3/ITD mutated genes is being carried In marrow leukaemia cell MV4-11 cell strains, the cell cycle point of compound 22 and compound 84 to these cell strains is tested The influence of cloth.With 0 μM of various concentration, 0.03 μM, 22,0.1 μM or 0.01 μM of the compound of 0.1 μM, 0.3 μM (in DMSO) The FLT3 kinase inhibitors AC220 of (in DMSO) acts on the acute myeloid leukemia cells in children for carrying FLT3/ITD mutators In MV4-11 cell strains, after acting on 24 hours, cell is collected, 1XPBS buffer solutions wash twice, and 75% ethyl alcohol is solid in -20 DEG C 24 hours fixed, 1XPBS buffer solutions wash twice again, and the PI dyeing liquors of 0.5mL 1XPBS buffer solutions and 0.5mL is added (to be purchased from the U.S. BD Bioscience) it dyes 15 minutes to being positioned over dark in cell and by cell and be protected from light 37 DEG C, with flow cytometer (BD FACS Calibur) detection cell cycle distribution (Fig. 4).
Experimental result is as shown in Figure 4：In the acute myeloid leukemia cells in children strain MV4- for carrying FLT3/ITD mutated genes In 11 cell strains, as the drug concentration of compound 22, compound 84 increases to 0.1 μM from 0 μM, the G0-G1 phases of capture it is thin Born of the same parents also increase respectively to 95.78%, 89.92% from 66.99%, 58.98%；The stronger FLT3 kinase inhibitors of selectivity The cell for the G0-G1 phases that AC220 is captured in 0.1 μM or 0.01 μM is respectively 96.53%, 90.49%；
Embodiment 131, which demonstrates compound 22 and compound 84, can will carry the acute myelogenous of FLT3/ITD mutators Leukaemia cell's MV4-11 cells prevent in the G0-G1 phases, and strong influence (Fig. 4) is distributed in cell cycle.
Embodiment 132：Acute myeloid leukaemia is treated using compound 22 and compound 77
In order to which detection compound 22 and compound 77 are in vivo to the inhibition of tumour, nude mice by subcutaneous lotus knurl mould is introduced Type.To more than 30 5 weeks big mouse (Balb/c-nu female mices are purchased from Shanghai Slac Experimental Animal Co., Ltd.) Inoculate MOLM-14 cells 1 × 107A/only, changes of weight and the gross tumor volume (gross tumor volume=swollen per day entry mouse Tumor length × tumour is wide2/2).After 10 days, wait for that mouse tumor volume reaches 200-400mm3, mouse is randomly divided into 3 groups, every group of 6- It 10, is treated as follows respectively：First group of daily oral administration gavage solvent (vehicle), i.e. methylcellulose base aqueous suspension (being purchased from Sinopharm Chemical Reagent Co., Ltd.)；The compound 22 and/or chemical combination of second group of daily oral administration gavage 12.5mg/kg The methylcellulose base aqueous suspension preparation of object 77；The compound 22 and/or compound of the daily oral administration gavage 25mg/kg of third group 77 methylcellulose base aqueous suspension preparation；The compound 22 and/or compound 77 of 4th group of daily oral administration gavage 50mg/kg Methylcellulose base aqueous suspension preparation；The same day of administration for the first time is denoted as the 0th day, successive administration observation 2 to 3 all (Fig. 5).
After experimental result with compound 22 to mouse as shown in figure 5, treated, the tumour growth of mouse is obviously pressed down System, the growth of mouse tumor volume significantly slow (Fig. 5 a)；After being treated to mouse with compound 77, the tumour growth of mouse is strong Strong to be suppressed (Fig. 5 b), the mouse tumor volume growth of 25mg/kg/ days groups significantly slows, and group mouse is swollen within 50.0mg/kg/ days Tumor hardly increases.The data of tumour transplatation mouse model prove compound 22 and compound 77 in Mice Body in the present embodiment It can play the role of very strong inhibition acute myeloid leukaemia (AML) tumour growth.
Industrial applicability
The present invention provides a kind of novel FLT3 kinase inhibitor compounds, can be used for reducing or inhibit cell or tested The FLT3 kinases and/or saltant type FLT3 kinase activities of person, and/or prevent or treat cell Proliferation venereal disease in subject Disease and/or FLT3 associated diseases.Thus, it can be made into corresponding drug, be suitable for commercial Application.
Although being explained in detail herein to the present invention, however, the present invention is not limited thereto, those skilled in the art can It is modified with principle according to the present invention, therefore, the various modifications that all principles according to the invention carry out all should be understood as Fall into protection scope of the present invention.

Claims (16)

1. the compound or its pharmaceutically acceptable salt of a kind of formula (II), have following structure：
N is 1 or 2；
Z is
R is selected from the C1-C6 ammonia that unsubstituted or carbon atom is optionally replaced by 1 to 3 independent R1, hetero atom is optionally replaced by R2 Two (C1-C4 alkyl)-N- (C1-C4) alkane that base alkyl and unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1 Base；
R1 is independently selected from hydroxyl and C1-C8 alkyl；
R2 is selected from C1-C8 alkyl.
2. the compound or its pharmaceutically acceptable salt of a kind of formula (IV), have following structure：
N is 1 or 2；
Z is
R is selected from the C1-C6 ammonia that unsubstituted or carbon atom is optionally replaced by 1 to 3 independent R1, hetero atom is optionally replaced by R2 Two (C1-C4 alkyl)-N- (C1-C4) alkyl that base alkyl, unsubstituted or carbon atom are optionally replaced by 1 to 3 independent R1；
R1 is C1-C8 alkyl；
R2 is C1-C8 alkyl.
3. the compound or its pharmaceutically acceptable salt of formula (II) according to claim 1, are selected from：
(S) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) the amyl- 1- ketone (12) of -4- methyl；
(R) -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -2- (dimethylamino) ethyl ketone (22)；
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) propyl- 1- ketone (24)；
(2R, 3R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) Piperidin-1-yl) the amyl- 1- ketone (25) of -3- methyl；
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) the amyl- 1- ketone (27) of -4- methyl；
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) pyrroles Alkane -1- bases) the amyl- 1- ketone (28) of -4- methyl；
(R) -2- amino -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- Base) ethyl ketone (43)；
(R) -2- amino -1- ((R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) -3-Hydroxybutanone (44)；
(R) -2- amino -1- ((R) 3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines - 1- yls) -3- espeletons (45)；
(R) -3- amino -1- (3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- Base) acetone (46)；
(R) -2- amino -1- ((R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) acetone (47)；
(R) -2- amino -1- ((R)-(3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazines Pyridine -1- bases) -3- hydroxypropanone-s (48)；
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidin-1-yl) -5- amino Pentanone (62)；
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) pyrrolidin-1-yl) -2- ammonia Base ethyl ketone (64)；
(R) -3- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) pyrrolidin-1-yl) -2- (two Methylamino) ethyl ketone (65).
4. the compound or its pharmaceutically acceptable salt of formula (IV) according to claim 2, are selected from：
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazan ammonia Base) acetamide (76)；
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) hexamethylenes Base) -4- methyl valeryls amine hydrochlorate (77)；
N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (methyl ammonia Base) acetamide (79)；
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cis- 1, 4- cyclohexyl) -4- methyl valeryls amine hydrochlorate (84)；
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) trans- 1, 4- cyclohexyl) -4- methyl valeryls amine hydrochlorate (85)；
(R) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) - 3- metlzylbutanamide Hydroclalorides (86)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -3- methyl - 2- (methylamino) butanamide hydrochloride (87)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino) -3- methylbutyryls amine (88)；
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) - 3- metlzylbutanamide Hydroclalorides (89)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -3- methyl - 2- (methylamino) butanamide hydrochloride (90)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino) -3- methylbutyryls amine (91)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -4- methyl - 2- (methylamino) valeryl amine hydrochlorates (92)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino) -4- methylpentanamides (93)；
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) - 4- methylpentanamides (94)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -4- methyl - 2- (methylamino) valeryl amine hydrochlorates (95)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino) -4- methylpentanamides (96)；
(R) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) - Butanamide hydrochloride (97)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (first ammonia Base)-butanamide hydrochloride (98)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino) butyramide (99)；
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) - Butanamide hydrochloride (100)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (first ammonia Base) butanamide hydrochloride (101)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino) butyramide (102)；
(R) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) - Valeryl amine hydrochlorate (103)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (first ammonia Base)-valeryl amine hydrochlorate (104)；
(R)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino)-pentanamide (105)；
(S) -2- amino-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) - Valeryl amine hydrochlorate (106)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (first ammonia Base)-valeryl amine hydrochlorate (107)；
(S)-N- (4- (4- amino-(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cyclohexyl) -2- (diformazans Amino)-pentanamide (108)；
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cis- 1, 4- cyclohexyl) -4- methyl -2- (methylamino) valeryl amine hydrochlorates (109)；
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cis- 1, 4- cyclohexyl) -4- methyl -2- (dimethylamino) pentanamide (110)；
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cis- 1, 4- cyclohexyl) -4- methyl valeryls amine hydrochlorate (111)；
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cis- 1, 4- cyclohexyl) -4- methyl -2- (methylamino) valeryl amine hydrochlorates (112)；
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) cis- 1, 4- cyclohexyl) -4- methyl -2- (dimethylamino) pentanamide (113)；
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) trans- 1, 4- cyclohexyl) -4- methyl valeryls amine hydrochlorate (114)；
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) trans- 1, 4- cyclohexyl) -4- methyl -2- (methylamino) valeryl amine hydrochlorates (115)；
(S) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) trans- 1, 4- cyclohexyl) -4- methyl -2- (dimethylamino) pentanamide (116)；
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) trans- 1, 4- cyclohexyl) -4- methyl -2- (methylamino) valeryl amine hydrochlorates (117)；
(R) -2- amino-N- (4- (4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) trans- 1, 4- cyclohexyl) -4- methyl -2- (dimethylamino) pentanamide (118).
Include compound according to any one of claim 1-4 or its is pharmaceutically acceptable 5. a kind of pharmaceutical composition Salt, pharmaceutically acceptable carrier or excipient and optional other therapeutic agents.
6. the compound according to any one of claim 1-4 is being prepared for treating proliferative disorders and/or FLT3 phases Purposes in the drug of related disorders.
7. purposes according to claim 6, wherein the illness is in response to FLT3 kinases or saltant type FLT3 kinase inhibitions.
8. purposes according to claim 7, wherein the saltant type FLT3 kinases is FLT3/ITD mutation type kinases.
9. purposes according to claim 6, wherein the proliferative disorders are selected from the presence or development of entity tumor.
10. purposes according to claim 6, wherein the proliferative disorders are selected from：B cell lymph cancer, sarcoma, diffusivity Lymph before large B cell lymphoid tumor, follicular lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, B cell Cell leukemia, lymphoplasmacytic lymphoma/macroglobulinemia Waldenstron, splenic marginal zone lymthoma, thick liquid cell Property myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, lymphoma mantle cell, Mediastinum (thymus gland) large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma, Lymphomatoid granulomatosis, breast ductal cancer, lobular carcinoma, gland cancer, melanoma, B cell proliferative disease, the cancer of the brain, kidney, liver Cancer, adrenal, carcinoma of urinary bladder, breast cancer, lymph cancer, gastric cancer, cancer of the esophagus, oophoroma, colorectal cancer, prostate cancer, cancer of pancreas, Lung cancer, carcinoma of vagina, film gland cancer, thyroid cancer, neck cancer, the cancer of CNS, glioblastoma, myeloproliferative disease, spongioblast Tumor, Huppert's disease, human primary gastrointestinal cancers, colorectal cancer, H/N tumors, epidermal hyper-proliferative, psoriasis, hyperplasia of prostate or on The tumor formation of skin feature, and combinations thereof.
11. purposes according to claim 6, wherein the proliferative disorders are selected from brain tumor.
12. purposes according to claim 6, wherein the proliferative disorders are selected from stomach neoplasm.
13. purposes according to claim 6, wherein the proliferative disorders are selected from lymthoma and leukaemia.
14. purposes according to claim 6, wherein the proliferative disorders are formed selected from tumor.
15. purposes according to claim 6, wherein the FLT3 associated diseases are selected from：It is Hodgkin's disease, myeloma, acute It is lymphocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic Granulocytic leukemia, chronic neutrophilic chronic myeloid leukemia, acute undifferentiated cell leukemia, anaplastic macrocytic lymph Tumor, human adult T cell ALL, it is integrated with the AML of three pedigree myelodysplasias, mixed type pedigree leukaemia, myelodysplasia Sign, myeloproliferative disorder, Huppert's disease and spinal cord sarcoma, chronic lymphocytic leukemia, diffusivity large B cell lymph Tumor, follicular lymphoma or chronic lymphocytic leukemia, lymphoma mantle cell, mediastinum (thymus gland) large B cell lymphoid tumor, blood vessel Interior large B cell lymphoid tumor, lymphoma primary effusion, Burkitt lymphoma, and combinations thereof.
16. compound according to any one of claim 1-4 is preparing for reducing or is inhibiting cell or subject Purposes in the drug of FLT3 kinases and/or saltant type FLT3 kinase activities.
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